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Education & Training

Junior Faculty Programs

Purpose of KL2 Program

The KL2 Award Program develops leaders in clinical research. Scholars are trained to design and oversee research in multidisciplinary team settings, skills critical to a successful career in translational science and the overall mission of the NIH.

Candidates are junior faculty, including clinical instructors and assistant professors, from CTSI partner institutions (i.e., Cedars-Sinai Medical Center, Charles R. Drew University of Medicine and Science, Lundquist Institute at Harbor-UCLA Medical Center, and UCLA). They must possess a doctoral-level research or professional degree and the potential to lead multidisciplinary teams. Scholars receive up to five years of support for mentored, multidisciplinary, patient-oriented research and training. 

In the first phase of training, scholars learn how to design and conduct clinical research studies as part of a team of scientists encompassing several disciplines. During the second phase of their training, scholars design and conduct clinical research projects under the guidance of mentors who have extensive experience in conducting clinical research. This training grant is unique, as all team members, including nurses, pharmacologists, biostatisticians and epidemiologists, learn together.

The award is designed to meet an important goal of UCLA CTSI: To provide the next generation of scientists with the training they need to conduct interdisciplinary research that impacts human health.

The Award

UCLA CTSI KL2 Translational Science awardees will receive annual support (see table below).  The award is renewable for up to a total of 3 years.  Continued support in years 2 and 3 will be contingent on performance during the prior year(s).

Scholar Salary (75% effort) $75,000
Scholar Fringe Benefits
Research Expenses (UCLA applicants must include TIF)
Tuition/Career Development (Excludes scientific memberships)
Statistical Support
$53,000
Travel for scientific conferences $2,000
MAXIMUM DIRECT COSTS/YEAR $130,000

The program emphasizes systems biology, clinical pharmacology and translational, community-partnered interventions to prepare trainees for interdisciplinary team science in all populations, across the life cycle. Diseases that disproportionately affect minority populations area particular focus.

Training and Career Development

The KL2 is led by four senior investigators with proven track records in basic, translational, and community-oriented research. This leadership structure provides representation in each aspect of trainee activity to ensure a balanced, innovative and technology-enabled approach to important problems in clinical medicine.

Each CTSI KL2 Trainee will be assigned CTSI co-mentor(s), and a customized career development program will be designed based on prior academic training and career development goals. The interdisciplinary mentors from the CTSI will work collaboratively with each proposing or primary mentor to maximize the content and quality of the training experience. The mentors and each CTSI KL2 Trainee will agree on a career development and research plan that will be updated each fellowship year.

Trainees will focus on a clinical problem and develop the required technological skills to approach the problem. Each trainee will select a three-person UCLA CTSI mentoring team with expertise in basic, clinical and community-based research. Mentors will be selected from a diverse potential pool of mentors and will provide research and career guidance. Trainees are expected to substantively participate in research over the duration of the award. With help from their mentors, the KL2 director, and the advisory committee, trainees will be responsible for designing and conducting their own research.

Through the K Scholars Society curriculum and their mentorship committee, trainees will gain insights into the molecular or systems basis of disease, the current state of medical care, novel technologies to improve the practice of medicine in communities, and state-of-the-art methods for conducting comparative effectiveness research. Research topics will be disease-based and individualized to each trainee. To facilitate future success, all trainees will receive intensive training in grant writing, career guidance, and will be integrated into teams of scientists who are developing larger proposals such as program project grants where a trainee may be able to “nest” their project in addition to submitting proposals as PI.

Trainees focusing on clinical pharmacology and therapeutics will experience a unique program emphasizing foundational concepts of bench to bedside to community translation, the main focus of the UCLA CTSI. This course of mentored investigation will also employ courses and mentored research in a systems biology approach to disease.

Eligibility Requirements

Eligibility Requirements
  • Possess a doctoral-level degree (e.g., MD, PhD, DDS, PharmD)
    • REQUIRED FOR PRE-APPLICATIONS: If the candidate has completed their terminal research degree (e.g. PhD) or end of post-graduate clinical training (e.g. residency, fellowship), whichever is later, before January 1, 2014, please describe the career path and experience since completion of training in the candidate’s NIH Biosketch’s Personal Statement.
  • Have a full-time junior faculty appointment at one of the four UCLA CTSI partnered institutions (UCLA, Cedars-Sinai, Charles R. Drew University, and Lundquist Institute at Harbor-UCLA) in any series at or above the clinical instructor level as of July 1, 2020.
  • U.S. citizen, non-citizen national or permanent resident at the time of application. Individuals on temporary or student visas are not eligible.
  • Commit 75% of professional effort to translational research. Those in surgical specialties may request a lower level of effort, but in no case lower than 50%, with the level of CTSI KL2 salary support being reduced proportionately. To request a lower level of effort, please contact CTSIWD@mednet.ucla.edu by the full application deadline, so a formal request can be submitted to the NIH.
  • Not be or have been a principal investigator on an NIH R01, or project leader on a subproject of a Program Project (P01), Center (P50, P60, U54), mentored career development grant (K23, K08, K01, etc.), or equivalent non-PHS peer reviewed research grant that is over $100,000 in direct costs per year. May have had support on a non-federal grant, a NRSA grant (F or T) or have been PI of an NIH small grant (R03 or R21). Note: Candidates may have had previous support on a K12 award, but the CTSI KL2 cannot extend total K support beyond five years.
  • Simultaneous KL2 and NIH K (e.g. K01, K08, K23, etc.) applications. If you have or will have a pending NIH K application, please see the table below for KL2 submission eligibility:
NIH K Submission Cycle Eligible for KL2 2020
May, June, July 2019 Yes
September, October, November 2019 Yes
January, February, March 2020 No

Application Checklist and Instructions

Use the below checklist as a guide when reviewing the Full Instructions and putting together materials for your submission.  Please note that the checklist represents the actual upload fields and documents that will be required in the online application.

Pre-Application

  • Deadline: December 2, 2019 by 5:00 PM.
  • Pre-Application is not required but highly recommended by the review committee.
  • Submission link will be available at: http://www.ctsi.ucla.edu/education/pages/kprogram and see “Request for Applications.”
  • Week of January 6, 2020: Applicants will receive general feedback on the pre-applications and decisions on whether to proceed with the full application
  • Pre-Application required components include:
    1. NIH-formatted Biosketch of CTSI KL2 candidate.
    2. NIH-formatted Biosketch of the primary mentor.
    3. Cover letter co-signed by the candidate and primary mentor to confirm their participation on the proposed project (1 page maximum).
    4. Specific aims of the proposed project (1 page maximum).
    5. List of three (3) training goals for the proposed application (150 characters with spaces maximum per goal).

Full Application Components

  1. NIH-formatted Biosketch of the CTSI KL2 candidate
  2. NIH-formatted Other Support Pages of the CTSI KL2 candidate
  3. Project Summary/Abstract (30 lines of text maximum)
  4. Specific Aims (1 page maximum)
  5. Program Plan (12 pages maximum)
  6. Authentication of Key Biological and/or Chemical Resources (1 page maximum)
  7. Protection of Human Subjects (required for research involving human subjects)
  8. Inclusion of Women, Minorities, and Inclusion Across the Lifespan (required for research involving human subjects)
  9. PHS Inclusion Enrollment Report (required for research involving human subjects)
  10. Data and Safety Monitoring Plan (required for research involving human subjects)
  11. Vertebrate Animals (when applicable)
  12. Training in the Responsible Conduct of Research (1 page maximum)
  13. Letters of Support from Mentoring Team (6 pages maximum)
  14. Institutional Letter of Support (2 pages maximum)
  15. Mentoring Team NIH-formatted Biosketches
  16. NIH-formatted Detailed Budget (Form Page 4) and Budget Justification
  17. Bibliography & References Cited
  18. Letters of Support for use of equipment, data, specimens, and community resources (when applicable).  Other letters of support submitted under this field will be removed during the administrative review process.

Full Application Instructions

Request for Applications (RFA)

2020 Application - Expected Timeline (subject to change).
Pre-Application Deadline (optional/recommended) December 2, 2019 by 5:00 PM Pre-Application Submission
Pre-Application Feedback & Decisions
Week of January 6, 2020
Full Application Deadline February 20, 2020 by 5:00PM
Interview Notifications Early May 2020
Selected Candidate Interviews Mid-late May 2020
Award Notifications End of May to early June 2020
Grant Start Date July 1, 2020

Please contact CTSIWD@mednet.ucla.edu if you encounter any technical issues with the application submission process or website.

See the CTSI announcement.

Other Resources

K Workshops

UCLA CTSI Education, Training and Career Development Program sponsors workshops for junior faculty planning to submit applications for KL2 and NIH K awards. See presentations from past workshops.

Need information about upcoming workshops? Contact CTSIWD@mednet.ucla.edu

Funding Search Tools, Grant-Writing Tips and Templates
Need tips or templates to assist with your grant writing? Visit the CTSI Funding Search Tools, Grant-Writing Tips and Diversity Supplements page.

Sample Applications 
UCLA CTSI has an online collection of successful applications that you can access anytime. See the Sample Applications and Letters of Support page for more information.

NIH K Kiosk

The NIH K Kiosk provides information and resources about career development awards available to young investigators. In addition to a list of open opportunities, the K Kiosk includes a “K Award Wizard” to help investigators choose the right opportunity, data on funded awards, and podcasts offering advice on career development.

The K Kiosk can be found by following this link: http://grants.nih.gov/training/careerdevelopmentawards.htm

Important NIH Notices

  • NHLBI Extension of Aggregate K Support for Physician Scientists (9/8/18). NHLBI has decided to extend the aggregate number of years of support for the K23 and K08 awards to 8 years of cumulative support on institutional and mentored Ks (e.g., K12 or KL2 plus the K08). Aggregate refers to all K-award support for a particular awardee coming from an institutional (e.g. KL2 or K12) plus a K08 or K23. This information can be found in the table of contacts of the relevant funding opportunities as listed below.
    • PA-18-372 Mentored Clinical Scientist Research Career Development Award (Parent K08 - Independent Clinical Trial Required)
    • PA-18-373 Mentored Clinical Scientist Research Career Development Award (Parent K08 - Independent Clinical Trial Not Allowed)
    • PA-18-374 Mentored Patient-Oriented Research Career Development Award (Parent K23 - Independent Clinical Trial Required)
    • PA-18-375 Mentored Patient-Oriented Research Career Development Award (Parent K23 - Independent Clinical Trial Not Allowed)
  • Career Award (K) Policy Update: Concurrent Support from a Mentored K Award and a Research Grant (NOT-OD-18-157, 4/9/18)
  • Clarification and Update: Salary Supplementation and Compensation on Research Career Development ("K") Awards (NOT-OD-17-094, 7/24/17)
  • Upcoming Updates to Application Instructions and Review Criteria for Research Grant Applications (NOT-OD-18-228, 9/14/18)
  • Upcoming Updates to Application Instructions and Review Criteria for Career Development Award Applications (NOT-OD-18-229, 9/14/18)
  • Requirement for Instruction in the Responsible Conduct of Research (NOT-OD-10-019, 11/24/09). The UCLA CTSI boilerplate can be found at https://ctsi.ucla.edu/funding/pages/boilerplates.

2019 Awardees

A. Lenore Ackerman, MD, PhD
Assistant Professor
Department of Surgery, Division of Urology
Cedars-Sinai Medical Center

Project title: The Urinary Microbiota and Host Inflammation in Lower Urinary Tract Symptoms.

Mentors:

David M. Underhill, PhD – Cedars-Sinai Medical Center
Jennifer T. Anger, MD MPH – Cedars-Sinai Medical Center
Dermot P. McGovern, MD PhD – Cedars-Sinai Medical Center
Suzanne Devkota, PhD – Cedars-Sinai Medical Center
Michael Freeman, PhD – Cedars-Sinai Medical Center

Multidisciplinary Expertise:
female pelvic medicine and reconstructive surgery, patient-reported outcomes, molecular immunology, cell biology, culture-independent microbial profiling, bioinformatics and data science, clinical phenotyping

Project Description:
A growing body of research into storage lower urinary tract symptoms (storage LUTS) -- highly prevalent, debilitating urologic conditions that include overactive bladder and interstitial cystitis/painful bladder syndrome -- suggests a potential role in disease development and progression for the diverse microbial communities of the urinary tract. To explore the pathophysiology of storage LUTS, we will examine the differences in these urinary bacterial and fungal communities and their interactions with host inflammatory responses, including an investigation of potential host genetic susceptibility factors associated with an increased risk of disease. The novel application of large-scale systems biology approaches to the urinary tract and the integration of these data with detailed clinical phenotyping is reshaping our understanding of these syndromes and will facilitate profound advances in the approach to clinical classification as well as the management and treatment of benign urologic conditions.


Paul Mathews, PhD
Assistant Professor
Department of Neurology
LA BioMed at Harbor-UCLA

Project title: Treating Ataxia Telangiectasia with Small Molecule Readthrough Compounds.

Mentors:

William (Bill) Boyle, PhD – UCLA
Richard Gatti, MD – UCLA

Multidisciplinary Expertise:
ataxia, neuroscience, drug development

Project Description:
Ataxia telangiectasia (AT) is a rare (~1 in every 100,000), but catastrophic and fatal inherited disease that is caused by a mutation in the ATM gene (AT mutated). No cure or effective treatments exist, therapy consists largely of palliation, and unfortunately, children born with this disease die by the age of ~25 yrs. Up to one third of disease-causing mutations in AT result from a Premature Termination Codon (PTC) in the mRNA encoded by the gene. We seek to demonstrate and develop a new therapeutic directed at overcoming PTCs to treat these AT patients. Our next steps are to screen our current candidate Small Molecule ReadThrough (SMRT) compounds and perform in vivo efficacy testing in a new mouse model of AT that expresses a disease causing PTC.


2018 Awardees

Steven J. Jonas, MD, PhD
Clinical Instructor
Department of Pediatrics
UCLA

Project title: Multifaceted nanosystems to accelerate the generation and clinical translation of cellular therapies.

Mentors:

Paul S. Weiss, PhD - UCLA
Donald Kohn, MD - UCLA
Ali Khademhosseini, PhD - UCLA

Multidisciplinary Expertise:
Nanoscience, materials science & engineering, materials chemistry, stem cell biology, cellular & gene therapies, pediatric hematology/oncology

Project Description:
We target the design and application of precision-assembled nanostructures that establish controlled and transient permeability of cells to create new tools to enable the broader clinical deployment of gene and cellular therapies. Immunotherapies that utilize T-cells engineered to recognize tumor antigens and to harness the immune system are emerging for these critically ill cancer patients. There is an unmet need for methods capable of processing large populations of these engineered cells quickly, cost effectively, efficiently, and with high recovery rates to generate more homogeneous and better characterized cellular products for clinical translation. Ideas inspired by microfluidics, nanolithography, and nanorobotics are combined with gene editing in this effort to generate broadly applicable and translatable methods for the rapid, efficient, and sustainable introduction of chimeric antigen receptor constructs in combination with gene-editing machinery into human T-cells.


Anusha Kalbasi, MD
Health Sciences Clinical Instructor
Department of Radiation Oncology
UCLA

Project title: Targeting radiation-induced myeloid cells in undifferentiated pleomorphic sarcoma.

Mentors:

Antoni Ribas, MD, PhD – UCLA
William McBride, PhD – UCLA
Fritz C. Eilber, MD - UCLA

Multidisciplinary Expertise:
Sarcoma, Radiation Oncology, Tumor Immunology & Immunotherapy, Macrophage and T cell Biology, Translational Clinical Trials, Murine Tumor Models

Project Description:
Up to 50% of patients with soft tissue sarcoma ultimately develop local disease failures or incurable distant metastases despite radiotherapy (RT) and surgery. The central premise of this proposal is that myeloid cells regulate the local and systemic anti-tumor effects of radiotherapy in undifferentiated pleomorphic sarcoma (UPS), a common soft tissue sarcoma. We will utilize both syngeneic murine models of UPS and patient specimens from an ongoing clinical trial to study these phenomena. We propose to characterize RT-induced myeloid cells in UPS and their impact on (1) local tumor control and (2) systemic anti-tumor T cell responses. Our approach will include high-dimensional cytometry, single cell proteomics, and multiple strategies to target myeloid subsets in combination with focal RT in murine models. We envision these studies will inform design of a clinical strategy to target myeloid subsets in combination with RT to improve local control, reduce metastases, and prolong survival.


Corrina Moucheraud, ScD, MPH
Assistant Professor
Department of Health Policy & Management
UCLA

Project title: Implementation and clinical effectiveness of cervical cancer prevention in Malawi: A critical evaluation to bring screening and treatment to scale.

Mentors:

Roshan Bastani, PhD – UCLA
Judith Currier, MD MSc – UCLA
Dr. Beth Glenn, PhD – UCLA

Multidisciplinary Expertise:
Implementation science, clinical outcomes research, cancer prevention and control

Project Description:
There is a vast and growing burden of non-communicable diseases in low-income countries, but little rigorous research about implementing and scaling-up effective strategies. Breakthroughs in clinical and translational science require accompanying implementation research to understand the real-world “how and why” of uptake and outcomes. Malawi has the highest rates of cervical cancer incidence and attributable mortality in the world; and, as in many low-resource settings, women typically present with advanced disease because they do not have access to cervical cancer screening. This research will use implementation science methods to identify strategies for reducing the excess burden of cervical cancer among women in Malawi. It will apply qualitative, quantitative and modeling methods in new ways to understand the implementation and effectiveness of cancer care delivery in this resource-limited health system. This project will build on a longstanding collaboration between UCLA and a Malawian health care organization, Partners in Hope.


Nicolaos Palaskas, MD, PhD
Clinical Instructor
Department of Medicine
UCLA

Project title: Targeting ferroptosis in resistant melanoma.

Mentor:

Tomas Ganz, PhD, MD – UCLA

Multidisciplinary Expertise:
Iron metabolism, cancer metabolism, animal models, bioinformatics, clinical hematology/oncology

Project Description:
New treatments are required for patients with metastatic melanoma that have progressed after MAPK pathway inhibition and immune therapies. Melanoma can evade these therapies through dedifferentiation. This process, which resembles epithelial-to-mesenchymal transition in carcinomas, is characterized by transcriptional reprogramming. Bioinformatic interrogation of a melanoma dedifferentiation signature in a large publicly-available pharmacogenomics database led to the discovery of a subtype-specific susceptibility to ferroptosis-inducing agents. This project aims to validate this computational lead, establish the in vivo efficacy of ferroptosis drugs, and study the mechanistic basis of ferroptosis in dedifferentiated melanomas.


Tanyalak Parimon, MD
Instructor
Division of Pulmonary and Critical Care Medicine
Cedars-Sinai Medical Center

Project title: Syndecan-1 Regulation of Lung Fibrosis.

Mentors:

Peter Chen, MD – Cedars-Sinai Medical Center
Cory Hogaboam, PhD – Cedars-Sinai Medical Center

Multidisciplinary Expertise:
Lung Biology, Exosome Biology, Lung Fibrosis

Project Description:
Idiopathic pulmonary fibrosis (IPF) is a fatal progressive lung disease. The overarching concept of IPF pathogenesis is that epithelial damage and dysregulated epithelial repair leads to perturbations of the lung microenvironment that induce various fibrogenic signals to recruit and activate various effector cells causing fibroproliferation. The critical knowledge gap in this paradigm is how epithelial dysfunction produces signals that coordinate effector cells in the pathogenic process. Syndecan-1 is primarily expressed by epithelial cells. Aberrancy of syndecan-1 expression leads to dysregulation of tissue repair. We found that syndecan-1 is overexpressed by the lung epithelium in IPF. We also demonstrated that syndecan-1 is pro-fibrotic in a murine bleomycin-injury model. Moreover, deviations to normal syndecan-1 expression levels promote lung fibrosis by altering miRNAs packaging in exosomes. The current project is to study the mechanisms by which syndecan-1 regulates miRNA loading into exosomes and to determine how syndecan-1 promotes fibrosis through exosomal miRNAs.


Joshua Sasine, MD
Clinical Instructor
Department of Medicine
UCLA

Project title: Outcomes and Mechanisms of Bidirectional EphB/ephrinB2 Decoupling in Multiple Myeloma.

Mentors:

John Chute, MD - UCLA
Ken Dorshkind, PhD - UCLA

Multidisciplinary Expertise:
Cancer biology, malignant microenvironment, stem cell regulation, hematopoietic cell transplant, chimeric antigen receptor (CAR) T-cells, clinical hematology-oncology

Project Description:
Multiple myeloma (MM) is the most common primary bone marrow malignancy and, despite advances in treatment, remains incurable. It resides almost exclusively in the bone marrow. Interactions between MM and the bone marrow microenvironment are essential for disease progression but the details of those interactions are not well understood. Bone marrow vascular endothelial cells (BMECs) strongly support myeloma and we hypothesized that this was due to a paracrine effect. Using tissue-specific endothelial cell screens and siRNA screens, we saw that the EphB/ephrinB signaling promoted MM through BMECs. EphB and ephrinB are cell surface tyrosine kinase receptors which initiate bidirectional signaling events in cells upon engagement. Loss of ephrinB2 in MM severely impaired MM growth in vivo. We will further examine the consequences of decoupling EphB/ephrinB2, evaluate the downstream molecular pathways responsible for this effect, and determine if this is a path to a pharmacologically tractable intervention.


Adam Schickedanz, MD, PhD
Assistant Professor
Department of Pediatrics
UCLA

Project title: The Impact of a Medical-Financial Partnership on Parent Health-Related Quality of Life and Child Developmental Risk Among Low-Income Families: A Randomized Controlled Trial.

Mentors:

Peter Szilagyi, MD, MPH - UCLA
Paul Chung, MD, MS - UCLA
Kenneth Wells, MD, MPH - UCLA
Doug Jutte, MD, MPH – UC Berkeley
Geri Ryan, PhD – RAND

Multidisciplinary Expertise:
Social Determinants of Health, Primary Care Clinical Redesign, Pediatric Health Services Research, Implementation Science

Project Description:
Poverty is a dominant driver of population health and health systems are increasingly addressing social determinants of health and social needs, such as food insecurity, housing insecurity, and other symptoms of financial hardship. Financial coaching is a standardized approach to improving family financial health through motivational interviewing and financial education, which has been proven to increase savings and reduce debt in low-income households. Our study will test whether there are health benefits to low-income families of addressing their financial hardship directly by providing them with financial coaching in addition to social needs navigation in a primary pediatric clinic. We will develop scalable approaches to clinical implementation of financial coaching and examine its effects on parent health-related quality of life, child developmental risk, and primary care utilization. Our study will inform the growing field of medical-financial partnerships through a national learning network of clinicians and financial capabilities professionals.


2017 Awardees

Jocelyn Kim, MD, PhD
Assistant Clinical Professor
Department of Medicine
UCLA

Project title: Understanding the mechanism of lentivector-based immunization.

Mentor:

Jerome A. Zack, PhD - UCLA

Multidisciplinary Expertise:
Immunology, Innate immunity, Virology, Signaling Transduction, Vaccines

Project Description:
Dendritic cells (DCs) are critical to stimulating adaptive immune responses owing to their superior ability to process antigens and present them to T cells. Methods have been devised to directly target antigen to DCs for immunization purposes. One effective strategy uses an HIV-1-derived lentiviral vector (LV) to deliver genes encoding antigen to DCs. The in vivo administration of this vector results in the selective expression of antigen in DCs and efficient priming of antigen-specific CD8+ T cells. However, the exact mechanism behind such efficient immunization is not clear. In this project we seek to understand how LVs perform two independent functions: delivery of antigen and activation of DCs. We expect to identify the mechanisms of LV antigen delivery, the immunostimulatory LV components and corresponding host innate immune signaling pathways. In addition, our findings will raise important questions regarding the nature of particles in vector preparations and discovery of novel immune agonists for vaccination.


John Mafi, MD, MPH
Assistant Professor-in-residence
Department of Medicine
UCLA &
Affiliated Natural Scientist
RAND Corporation

Project title: Leveraging Electronic Health Records to Develop the Next Generation of Quality Measures: eMeasures of Low Value Care

Mentors:

Catherine Sarkisian, MD, MSPH - UCLA
Cheryl Damberg, PhD - RAND Corporation

Multidisciplinary Expertise:
Quality Measurement and Improvement, Appropriateness of Care, Electronic Health Records.

Project Description:
This project seeks to develop electronic health record-based measures of low value care (“eMeasures”), which will be critical for ongoing efforts to improve the quality and value of U.S. healthcare delivery. The work will also evaluate important correlates of low value care, which will help inform future interventions aiming to safely reduce wasteful spending and prevent patient harm from unnecessary care. The long-term goal of the project is to leverage electronic health records in order to build a new generation of low value care eMeasures, which ultimately become the prototype for a new national standard of quality measurement.


Claudio Scafoglio, MD, PhD
Assistant Project Scientist
Department of Medicine
UCLA

Project title: The role of sodium-dependent glucose transport in early-stage lung adenocarcinoma: diagnostic and therapeutic implications

Mentors:

Steven Dubinett, MD - UCLA
David Shackelford, PhD - UCLA
Jorge Barrio, PhD - UCLA
Ernest Wright, PhD - UCLA
Thomas Graeber, PhD - UCLA
Dean Wallace, MD - UCLA
David Elashoff, PhD - UCLA

Multidisciplinary Expertise:
PET Imaging, Oncology, Cancer Metabolism, Translational Research, Pre-clinical Trials in Mouse Models, Lung Pathology, Lung Carcinogenesis.

Project Description:
My project is focused on the role of sodium-dependent glucose transporter 2 (SGLT2) in early-stage lung adenocarcinoma. SGLT2 functions independently of the widely described glucose transporter (GLUT) system, and represents a previously unknown means for malignant cells to sustain their increased need for glucose. My preliminary studies have shown that SGLT2 is expressed in pre-neoplastic and early-stage lung adenocarcinoma (LADC). This is important because high-resolution computed tomography (CT) is very sensitive in detecting early-stage, asymptomatic lung lesions, but it is not specific and cannot distinguish between benign and malignant lesions. Positron-emission tomography (PET) with 2-[F] fluoro-2-deoxyglucose (F-FDG), which detects GLUT activity, is used to stage advanced ADC, but cannot effectively detect early lesions; however, F-FDG does not measure SGLT activity. To study SGLT-mediated glucose transport in pre-malignancy and early-stage lung adenocarcinoma, we use a radio-labeled positron emission tomography (PET) probe, methyl-4-[F] fluorodeoxyglucose (F-Me4FDG), specific for SGLTs. This novel tracer has the potential to complement F-FDG in the diagnosis of early-stage lung tumors. In addition, F-Me4FDG PET can be used to identify SGLT2-active tumors, which may be targeted using FDA-approved SGLT2 inhibitors, the gliflozins. I am going to carry on a pre-clinical validation of F-Me4FDG PET as a translational imaging-based platform to non-invasively identify pre-malignancy and early-stage SGLT2-active lung tumors likely to benefit from treatment with gliflozins.


Christopher Seet, MD
Clinical Instructor
Department of Medicine
UCLA

Project title: Development of a novel platform for the discovery of antigen specific TCRs

Mentors:

Dr. Gay Crooks - UCLA
Dr. Owen Witte - UCLA

Multidisciplinary Expertise:
Immunology, stem cell biology, cancer immunotherapy, cellular therapy, clinical hematology/oncology.

Project Description:
Engineered T cell immunotherapies offer unprecedented potential in the treatment of cancer. Identification of high-affinity T cell receptors (TCRs) that recognize public tumor-associated antigens (TAAs) may facilitate the rapid development of new T cell therapies for cancer. Identification of these TCRs from patient samples however is difficult, as TAA-reactive T cells are typically deleted in the thymus through negative selection. We have developed a novel artificial thymic organoid (ATO) system that permits the efficient in vitro generation of T cells from human hematopoietic stem cells. We hypothesize that T cells generated in ATOs are not subject to conventional negative selection and are thus a unique source of high-affinity TAA-reactive TCRs. In this project, I will optimize an ATO-based platform for the discovery of TCRs specific for model public tumor antigens; characterize the binding affinity and anti-tumor efficacy of ATO-derived TCRs; and validate this system through the proof-of-concept capture of TCRs against clinically relevant TAAs for which the isolation of high-affinity TCRs has been challenging. A platform for the rapid identification of high-affinity TAA-reactive TCRs would be readily translatable to clinical applications in cancer immunotherapy.


Michifumi Yamashita, MD, PhD
Assistant Professor
Department of Pathology and Laboratory Medicine
Cedars-Sinai Medical Center

Project title: Role of EGF Receptor in TLR7-mediated Glomerulonephritis

Mentors:

Moshe Arditi, MD - Cedars-Sinai Medical Center
David M. Engman, MD, PhD - Cedars-Sinai Medical Center

Multidisciplinary Expertise:
Glomerulonephritis, Toll-like receptor (TLR) signaling, Epidermal Growth Factor Receptor (EGFR), innate immunity, Nephrology, Renal pathology,

Project Description:
Glomerulonephritis (GN) is a group of inflammatory diseases in kidney glomeruli, a filtering system for blood to generate urine. GN is associated with significant morbidity and mortality, and is highly prevalent: it affects 0.12% of the general population and 1.2% of the older population, and often results in dialysis-requiring end-stage renal disease, hospitalization, or death. Epidermal Growth Factor Receptor (EGFR), a receptor tyrosine kinase, is necessary for a rapidly progressive malignant form of GN. We will investigate the critical signaling pathway for GN at the molecular and functional levels using a cell culture system, dissect the pathomechanism of GN and study the therapeutic application of substances that inhibit EGFR in a mouse model of malignant GN. To translate this work into a potential treatment for humans, we will seek to identify the subtypes of human GN that could be good candidates for EGFR inhibitor therapy using kidney biopsy samples.


Pamela Yeh, PhD
Assistant Professor
Department of Ecology and Evolutionary Biology
UCLA

Project title: Using Systems Biology Approaches to Combat the Evolution of Multi-Drug Resistant Pathogens

Mentors:

Robert Damoiseaux, PhD, UCLA
Harvey Herschman, PhD, UCLA
Barbara Natterson-Horowitz, MD, UCLA

Multidisciplinary Expertise:
Experimental Evolution, Microbial Ecology, Systems Biology, Antibiotic Resistance, Multiple Stressors, Drug Interactions, Emergent Properties, Higher-order Interactions.

Project Description:
The evolution of multi-drug resistant pathogens is an urgent and growing global health issue. Here we tackle the challenge of antibiotic resistance in three ways, combining evolutionary perspectives and systems biology concepts with high throughput experimental capabilities. First, we investigate how antibiotics that are typically only used in gram-positive bacteria can be effectively used as novel treatments in gram-negative bacteria via synergy with other drugs. Second, we examine higher-order interactions that occur among more than two-drug combinations in order to discover and determine synergistic and antagonistic interactions to employ against pathogens. Finally, we will determine mechanisms of action and mechanisms of synergy using mutagen-antibiotic combinations. Our overarching goal is to find novel methods and treatment strategies to combat the evolution of drug-resistant bacteria.


Bo Yu, DDS, PhD
Assistant Professor
UCLA School of Dentistry
UCLA

Project title: The Effect of Nanoparticle-Encapsulated Resveratrol for Treatment of Periodontitis.

Mentors:

Cun-Yu Wang, DDS, PhD – UCLA
Ben Wu, DMD, PhD – UCLA

Multidisciplinary Expertise:
Molecular biology, bone biology, bioengineering

Project Description:
Periodontitis is the most common osteolytic disease that afflicts approximately 50% of the population over the age of 30. Aside from destruction to local periodontal tissue and loss of tooth support, periodontitis is also a risk factor for many systemic diseases such as diabetes, cardiovascular diseases and oral cancer. Unlike the conventional treatment that focuses on removal of pathogens, this project aims to develop a novel approach using reseveratrol (grape extract)-loaded nanoparticles locally placed under the gum line to target periodontal inflammation, the actual mediating mechanism underlying periodontal tissue destruction. The study will investigate if reseveratrol will inhibit bone resorption and inflammation via upregulation of PGC-1α gene; the efficacy and safety of nanoparticles will also be evaluated in a murine model.


2016 Awardees

Elizabeth Barnert, MD, MPH, MS
Assistant Professor-in-Residence
Department of Pediatrics
UCLA

Project title: Promoting Access to Behavioral Health Services for Youth Transitioning Home After Incarceration

Mentors:

Paul Chung, MD, MS - UCLA
Laura Abrams, PhD - UCLA
Bonnie Zima, MD, MPH

Multidisciplinary Expertise:
Juvenile Justice, General Pediatrics, Behavioral Health, Community-Partnered Research

Project Description:
This project explores youths’ access to community-based behavioral health services during reentry, the vulnerable period following a youth’s release from juvenile incarceration. Up to 70% of incarcerated youth have at least one behavioral health disorder. These disorders increase future incarceration risk, and incarceration and reentry likely have negative effects on behavioral health. Despite the existence of effective, evidence-based behavioral health programs tailored for these youth, reentry youth are at enormous risk for poor health, education, and employment outcomes, and typically experience poor access to community-based behavioral health services. During Phase I, we will use a mixed methods approach to describe youth and parent perspectives on reentry youths’ behavioral health needs and access to community-based behavioral services. During Phase II, we will engage community stakeholders to develop and pilot test a family-centered intervention, such as a transitions life coach intervention, to promote youths’ access to community-based behavioral health services during reentry.


John K. Lee, MD, PhD
Health Sciences Clinical Instructor
Division of Hematology/Oncology
UCLA

Project title: Dissecting the function of Myc paralogs in human prostate cancer

Mentors:

Owen Witte, MD - UCLA

Collaborators:

James Wohlschlegel, PhD – UCLA
Justin Drake, PhD – Rutgers
Josh Stuart, PhD – UC Santa Cruz

Multidisciplinary Expertise:
Cancer biology, proteomics, genomics/transcriptomics, functional genetic screening

Project Description:
Myc proteins are multi-functional transcription factors whose deregulation is central to the initiation and maintenance of most human cancers. They are broadly thought to have redundant functions in development and tumorigenesis. In prostate cancer, the amplification and overexpression of c-Myc are common in prostate adenocarcinomas while N-Myc is amplified and overexpressed in 40% of neuroendocrine prostate cancers (NEPC). Prior work using a tissue recombination assay has shown that ectopic expression of c-Myc and activated AKT1 in human prostate epithelial cells produces poorly differentiated adenocarcinoma and squamous cell carcinoma while N-Myc and activated AKT1 generates mixed NEPC and prostate adenocarcinoma. These findings indicate that Myc paralogs may drive the pathogenesis of discrete cancer phenotypes through distinct biologic functions mediated by their regulatory complexes. The objective of this work is to characterize the core and divergent functions of c-Myc and N-Myc in prostate cancer through interactome, transcriptome, proteome, phosphoproteome, and functional analyses.


Ali Zarrinpar, MD, PhD
Assistant Professor
Division of Liver and Pancreas Transplantation
UCLA

Project title: The Role of Neutophil Activation in Hepatic Ischemia-Reperfusion Injury

Mentors:

Jerzy Kupiec-Weglinski, MD, PhD – UCLA
Steven Bensinger, DVM, PhD – UCLA

Multidisciplinary Expertise:
Liver Transplantation, Liver Disease, Inflammation, Neutrophils, Cytokines, Cell and Molecular Biology, Signal Transduction, Ischemia-Reperfusion Injury

Project Description:
Ischemia/reperfusion injury is the principal mechanism of organ damage in transplantation, heart attacks, strokes, and other vascular diseases. It is a multifactorial inflammatory process that occurs without any exogenous antigens and instigates a series of innate immune-related responses that can result in cell damage, cell death, and organ failure. Neutrophil activation is a major effector cell in ischemia/reperfusion injury. Our proposal probes the connections between a key signaling molecule, Bruton’s tyrosine kinase, and the activation of neutrophils, as well as how these interactions and their effects lead to liver ischemia/reperfusion injury. We intend to do this using a murine model, as well as by studying specimens obtained at the time of surgery from human liver transplant recipients. By understanding the mechanisms through which the activation of neutrophils can be inhibited or modified, we can derive new therapies to prevent or treat ischemia/reperfusion injury.


2015 Awardees

Kara Calkins, MD, MSCR
Assistant Professor
Division of Neonatology
UCLA

Project title: A Predictive Model for Pediatric Parenteral Nutrition Associated Cholestasis Using Novel Biomarkers: Plasma Phytosterols, Cytokines, and Bile Acids and Erythrocyte Omega-6:Omega-3 Ratios

Mentors:

Sherin Devaskar, MD – UCLA
David Elashoff, PhD – UCLA

Multidisciplinary Expertise:
Pediatrics, hepatology, nutrition and metabolism, biomarker discovery, biomathematics

Project Description:
Parenteral nutrition (or intravenous nutrition) is associated with a potentially lethal liver disease—parenteral nutrition associated cholestasis (PNAC). Neonates are highly susceptible to PNAC. Liver biopsies and serum direct bilirubin are standard tests for PNAC diagnosis, but they have limitations. There is a need to develop leading biomarkers as diagnostic tools that reflect early liver injury. I have supporting evidence that high concentrations of phytosterols, omega-6:omega-3 fatty acid ratios, and cytokines impede biliary flow, resulting in an increase in bile acids. In a cohort of infants at high risk for PNAC, I will: 1.) assess changes in these biomarkers over time, and 2.) determine if a profile of biomarkers in combination with clinical risk factors can predict PNAC. Should my hypothesis be correct, a biomarker profile could be used pro-actively to sub-select patients at high risk for PNAC so that therapeutic modalities could begin in a timely manner.


Kara Chew, MD, MS
Assistant Clinical Professor
Division of Infectious Diseases
UCLA

Project title: Impact of Hepatitis C Co-infection on Cardiovascular Risk in HIV-infected Persons

Mentors:

Judith S. Currier, MD, MSc – UCLA
Debika Bhattacharya, MD, MS – UCLA
Raymond T. Chung, MD – Harvard Medical School, Massachusetts General Hospital
David Elashoff, PhD – UCLA
C. Noel Bairey Merz, MD – Cedars-Sinai Medical Center
Steven-Huy Han, MD – UCLA

Multidisciplinary Expertise:
Infectious disease, cardiovascular disease, liver disease, inflammation

Project Description:
In the current era of effective antiretroviral therapy (ART) and aging HIV-infected patients, cardiovascular disease (CVD) and other non-AIDS complications are responsible for an increasing number of deaths. CVD risk is increased in HIV-monoinfected persons and HCV coinfection, as a second chronic viral infection with associated immune activation and inflammation, as well as known metabolic derangements, may further increase this risk. The proposed study will establish a multi-site prospective, longitudinal cohort of sociodemographically diverse HIV/HCV-coinfected and matched HIV-monoinfected men and women with HIV suppressed on stable ART to investigate the impact of HCV coinfection on CVD risk assessed by endothelial function and soluble CVD biomarkers and the potential for HCV treatment to improve CVD outcomes, as well as explore macrophage activation as a mediator of endothelial dysfunction in HIV/HCV.


Tom Davidson, MD
Assistant Professor
Division of Pediatric Hematology-Oncology
UCLA

Project title: Dendritic Cell Vaccination for Newly Diagnosed Pediatric High-Grade Glioma Patients

Mentors:

Linda Liau, MD, PhD - UCLA
Robert Prins, PhD - UCLA

Multidisciplinary Expertise:
Pediatrics, Hematology-Oncology, Neuro-Oncology, Tumor Immunology, Translational Cancer Research, Immunotherapy, Clinical Trials.

Project Description:
Brain tumors in the pediatric population have poor prognosis and account for the highest mortality rate of all childhood cancers. High grade gliomas (HGG) remain the biggest challenge, with few treatment options and an overall 5-year survival rate of 10-30%. A potential alternative to conventional treatments is utilizing a patient’s own immune system to target and eliminate tumor cells. In this study, dendritic cells (DC) isolated from the subject's own blood will be co-cultured with tumor lysate. These stimulated DCs will then be injected back into the patient as a vaccine in order to teach the host immune system to “recognize” the malignant brain tumor cells as “foreign” to the body. We propose that this will help instruct the patient’s own immune system to attack any residual tumor cells. We hypothesize that DC vaccination for pediatric HGG patients will induce better outcomes than current standard therapies with chemotherapeutics and radiation alone.


Siwen Hu-Lieskovan, MD, PhD
Clinical Instructor
Division of Hematology & Oncology
UCLA

Project title: Mechanistic Study of Combined Targeted Therapy and Immunotheray for Melanoma

Mentors:

Antoni Ribas, MD, PhD – UCLA
John Glaspy, MD, MPH – UCLA
Steven Dubinett, MD – UCLA

Multidisciplinary Expertise:
Tumor Immunology, Translational Cancer Research, Cell and Molecular Biology, Signaling Transduction, Clinical Trials.

Project Description:
Recent breakthrough of immune checkpoint inhibition has resulted in durable disease control of metastatic cancers in a small subset of patients, and BRAF and MEK inhibitors can induce highly frequent tumor responses in patients with BRAFV600E mutant melanoma, but of limited durability. BRAF and MEK inhibitors can sensitize the immune system to target tumors, providing the rationale to synergize with immunotherapy for durable response in majority of patients. Our pre-clinical studies using syngeneic BRAFV600E mutant melanoma mouse model showed significantly improved antitumor effect combining BRAF inhibitor dabrafenib and MEK inhibitor trametinib, with either pmel-1 adoptive cell transfer or anti-PD1 immunotherapy, with increased tumor infiltrating lymphocyte, preserved effector function, and favorable changes in the tumor milieu. Based on these results, three Phase I trials have been opened at UCLA testing the combination of BRAF and MEK inhibitors with anti-PD-1/L1 antibodies. I proposed to study the clinical relevance of the preclinical findings in paired pre- and post-dosing biopsies that we have been collecting in these trials.


Biren Kamdar, MD, MBA, MHS
Health Sciences Assistant Clinical Professor
Division of Pulmonary and Critical Care Medicine
UCLA

Project title: A MICU Sleep Promotion Intervention Using Actigraphic Outcome Assessment

Mentors:

Michael Ong, MD, PhD – UCLA
Jennifer Martin, PhD – UCLA
Dale Needham, MD, PhD – Johns Hopkins University
Nancy Collop, MD – Emory University

Multidisciplinary Expertise:
Quality Improvement, Actigraphy, ICU Outcomes, Sleep in the ICU, Implementation Methods.

Project Description:
Poor sleep is common in the intensive care unit (ICU) and is felt to contribute to adverse patient outcomes, including delirium. To address this problem, we will implement a sleep promoting intervention in the RRUMC medical ICU (MICU). Using an established, multi-disciplinary approach, and a before-after study design, this intervention will involve three incremental sleep improvement Stages: 1) environmental interventions (minimization of noise, light, and patient disturbances); 2) non-pharmacologic interventions (earplugs, eye masks, soothing music), and 3) a guideline promoting use of appropriate pharmacologic sleep aids. This study aims to extend a prior improvement effort into a new hospital system, and to evaluate its effect on delirium and actigraphic estimates of sleep. The use of actigraphy, a wristwatch-like accelerometer device used to assess activity and sleep, represents a novel application of an established research tool, and poses a practical option for sleep estimation during this and future ICU intervention efforts.


Kindra Kelly-Scumpia, PhD
Assistant Project Scientist
Division of Dermatology
UCLA

Project title: Regulation of myeloid cell development during cutaneous immune responses

Mentors:

Robert Modlin, MD – UCLA
Maria Ochoa, MD – UCLA
Steven Dubinett, MD – UCLA
Harvey Herschman, PhD – UCLA
Matteo Pellegrini, PhD – UCLA
David Elashoff, PhD - UCLA

Multidisciplinary Expertise:
Immunology, host defense, type I interferon, skin immunity, infection

Project Description:
Leprosy is a human skin disease caused by the bacteria Mycobacterium leprae (mLEP) that presents with a range of clinical systems that correlate with the immune response to the bacteria making it an ideal model to study skin immunity. The goal of this proposal is to determine mechanisms by which developing myeloid cells can be polarized into various effector cells by factors identified in the skin of leprosy patients. Preliminary data identifies, IL-34, as a potential factor contributing to polarization into a suppressive phenotype, as it is increased in skin lesions from the progressive form of leprosy (L-lep) compared to the self-limiting or tuberculoid form (T-lep). IL-34 can drive IL-10 production in early Tie-2 expressing progenitors and monocytes upon mLEP stimulation. Studying mechanisms leading to differences in the two forms of leprosy has the potential to lead to novel therapies for cutaneous inflammatory diseases.


Rajan Kulkarni, MD, PhD
Clinical Instructor
Division of Dermatology
UCLA

Project title: Determination of Single-Cell Heterogeneity of Circulating Tumor Cells in Cancer

Mentors:

Matthew Rettig, MD – UCLA
Dino Di Carlo, PhD – UCLA
David Elashoff, PhD – UCLA

Multidisciplinary Expertise:
Cancer, Metastasis, Circulating Tumor Cells, genomics/transcriptomics, bioengineering

Project Description:
Cancer can pose a significant burden when in advanced stages or recurrent; the Vortex Chip technology that we have developed provides a non-invasive method to collect circulating tumor cells (CTCs) and can serve as a source of cells to study tumor cell heterogeneity. Understanding heterogeneity in cancer, particularly at the single cell level, will be important in understanding tumor evolution and in predicting response to treatments and this work aims to examine single cell heterogeneity through capture of CTCs from patients with advanced cancer and to validate its use for determining molecular and genetic information. Such information will allow for improved understanding of cancer and may assist in development of more specifically targeted treatments.


Michelle Rozenman, PhD
Health Sciences Clinical Instructor
Department of Psychiatry and Biobehavioral Sciences
UCLA

Project title: Extinction Learning as Facilitator of Cognitive Bias Modification for Youth Anxiety

Mentors:

John Piacentini, PhD – UCLA
Michelle Craske, PhD – UCLA

Multidisciplinary Expertise:
Anxiety disorders, child and adolescent psychology, experimental therapeutics, fear learning

Project Description:
Anxiety is a chronic and debilitating condition that affects up to 30% of youth. As anxious individuals interpret ambiguous information as threatening, researchers have begun to directly modify interpretation with the use of computerized cognitive bias modification interventions (CBM-I), which are proposed to reduce anxiety by training more benign, rather than threatening, cognitive associations. The current study involves a randomized controlled trial of CBM-I, as compared to a computerized control condition, to treat youth anxiety and simultaneously test whether the intervention works by extinguishing cognitive fear associations. Anxious youth (ages 10 to 17) will be randomly assigned to 12 sessions of either a personalized CBM-I program or a computerized control condition. Anxiety, interpretation bias, and physiological arousal during a fear paradigm will be assessed at pre-, mid-, and post-treatment to explore extinction learning as a putative mechanism underlying CBM-I efficacy. Findings have immediate clinical implications for potential use of CBM-I as stand-alone intervention, as well as an augmentation to exposure-based therapy.


Priya Uppuluri, PhD
Assistant Professor
Division of Infectious Diseases
LA BioMed/Harbor-UCLA

Project title: Chemical Genomics Screen to identify Inhibitors of Candida albicans biofilm

Mentors:

Ashraf Ibrahim, Ph.D – LA BioMed/Harbor-UCLA
John E. Edwards, MD – LA BioMed/Harbor-UCLA
Robert Damoiseaux, PhD – UCLA

Multidisciplinary Expertise:
Infectious diseases, Chemical genomics, Drug development

Project Description:
The fungus Candida albicans is the third leading cause of intravascular catheter-related infections, most of which are due to the presence of biofilms in these devices. Cells in biofilms display high levels of resistance to most antifungal agents and prolong infections by providing a safe sanctuary from which organisms can seed new infection sites. Thus, dispersal of cells from biofilms becomes a significant phenomenon, predisposing susceptible patients to life threatening disseminated candidiasis. The goal of this proposal is to inhibit the process of biofilm dispersal by screening hundreds of FDA approved small molecule drugs, in novel, high-throughput biofilm assays. Short-listed molecules will be validated in a unique catheterized mouse model of biofilm formation, for their potency to inhibit biofilm-associated dissemination in vivo. Overall, this study will provide novel drug candidates that will supplement the rapidly shrinking antifungal-drug armory against C. albicans biofilms.


2014 Awardees

Nicholas M. Bernthal, MD
Assistant Professor
Department of Orthopaedic Surgery
UCLA

Project title: Novel Antibacterial Coatings Preventing Implant Infections

Mentors:

John Adams, MD – UCLA
Jeff Miller, PhD – UCLA
Moshe Arditi, MD – Cedars–Sinai Medical Center
George Liu, MD – Cedars–Sinai Medical Center
Lloyd Miller, MD, PhD – Johns Hopkins Medicine

Multidisciplinary Expertise:
Inflammation, Infectious Disease, Orthopaedic Surgery, Bioengineering, Immunology

Project Description:
Implant infection after orthopaedic surgery is devastating to patients, leading to multiple reoperations and increased morbidity and mortality. These infections are also an enormous burden to our health system, comprising more than $8 billion in additional health care spending. This project will explore novel antimicrobial coatings aimed at reducing the incidence and virulence of implant infection. We will utilize a novel mouse model of orthopaedic implant infection to assess in vivo efficacy and safety of these coatings and analyze effects on osseointegration. We will also examine the mechanism of bacterial evasion of antimicrobial effects. In sum, this project will provide the groundwork for developing an effective, well-tolerated antimicrobial coating ready for large animal study and/or human clinical trial.


Hyong Jin Cho, MD, PhD
Assistant Professor
Semel Institute for Neuroscience and Human Behavior
UCLA

Project title: Sleep Loss as a Vulnerability Factor for Inflammation-Induced Depressive Symptoms in Older Women

Mentors:

Michael Irwin, MD - UCLA
Steve Cole, PhD - UCLA
Naomi Eisenberger - UCLA

Multidisciplinary Expertise:
Psychoneuroimmunology, sleep disturbance, depression, fatigue, aging research, epidemiology

Project Description
Sleep disturbance and depression in older adults – especially in older women – are major public health burdens because both conditions are highly prevalent and associated with morbidity, functional decline, and mortality. Although the association between these two conditions is well known, the mechanisms of this association are poorly understood. Dr. Cho’s project aims to examine the potential causal contribution of sleep loss to depressive symptoms via inflammatory mechanisms in older women, by means of experimentally induced sleep deprivation and systemic inflammation. Specifically, it is hypothesized that sleep loss is a vulnerability factor for inflammation-induced depressive symptoms in older women, and this hypothesis will be examined by partial sleep deprivation followed by endotoxin challenge. The findings of this study may guide future clinical studies in identifying individuals at risk of developing depression when exposed to heightened inflammatory states such as aging, obesity, and chronic disease and also in developing prevention strategies for late-life depression.


Eugenio Cingolani, MD
Assistant Professor-in-Residence
Division of Cardiology, Electrophysiology Section
Cedars-Sinai Medical Center Heart Institute

Project title: Biological Pacemaker in a Pre-Clinical Model of Heart Block

Mentors:

Eduardo Marb?n, MD, PhD - Cedars-Sinai Medical Center
Sumeet Chugh, MD - Cedars-Sinai Medical Center
Hee Cheol Cho, PhD - Cedars-Sinai Medical Center

Multidisciplinary Expertise:
Cellular biology, molecular biology, gene therapy, cellular electrophysiology, clinical cardiac electrophysiology, cellular mechanisms of arrhythmias

Project Description
Abnormally slow heart rhythms affect many people in the USA, and those numbers are steadily increasing as the population ages. While electronic pacemakers are the mainstay of therapy for these conditions, complications from device implantation, such as life-threatening infections, may occur. As an alternative to electronic devices, we propose to study select biological pacemaker candidates in a pre-clinical model, and to develop the most promising candidate as a potential therapeutic agent for first-in-human application.

Gene-based BioP were first described more than a decade ago; somatic gene transfer of various constructs has shown to create BioP activity. However, until recently, in-vivo preclinical applications have been mostly limited to highly-invasive open-chest models. We have developed a clinically-realistic minimally-invasive delivery technique and used it to create BioP in a porcine model of complete heart block. We propose to use this approach to compare two “finalist” therapeutic candidates with fundamentally different mechanisms of action.


Tiane Dai, MD, PhD
Assistant Professor
Division of Nephrology
LA BioMed/Harbor-UCLA

Project title: An innovative approach to the preserve peritoneal membrane

Mentors:

Sharon Adler, MD – LA BioMed/Harbor-UCLA
Isidro Salusky, MD – UCLA
Cynthia Nast, MD – Cedars-Sinai Medical Center
Youngju Pak, PhD – LA BioMed/Harbor-UCLA

Multidisciplinary Expertise:
Nephrology, pathology, pharmacodynamic methodology, cell and molecular biology and biostatistics

Project Description
Peritoneal dialysis (PD) is more cost-efficient and offers a better quality of life than hemodialysis (HD) for patients with end stage renal disease, but long-term utilization is limited by membrane failure. The standard osmotic agent that drives fluid removal in PD is dextrose, which is one of the most important causes of long-term peritoneal membrane injury and functional loss. Although a maltose polymer (icodextrin) improves fluid removal, it does not improve actual dialysis, nor has it reduced inflammation. Our preliminary data from cell cultures, animal studies and human PD effluent has implicated JAK/STAT signaling in PD fluid-induced peritoneal inflammation and injury. This proposal will test whether JAK/STAT inhibition preserves peritoneal membrane structure and function in rats and inhibits inflammation in patients. Together, these data may provide support for Phase 2 testing in PD patients.


Thanh Neville, MD, MSHS
Assistant Clinical Professor
Division of Pulmonary and Critical Care Medicine
UCLA

Project title: Understanding Inappropriate Treatment in Critically Ill Patients

Mentors:

Neil Wenger, MD, MPH – UCLA
Derjung Mimi Tarn, MD, PhD - UCLA
Chi-Hong Tseng, PhD – UCLA
Eric Kleerup, MD - UCLA

Multidisciplinary Expertise:
Critical care, pulmonary medicine, ethics, and end-of-life research

Project Description
Advances in medicine have enabled the ICU to save lives as well as prolong the dying process. Inappropriate treatment, defined here as a treatment that should not be provided because it does not offer the patient benefit, can prolong suffering, cause family distress, damage the healthcare team morale, and transform death into an undignified process. In this proposal, Dr. Neville aims to characterize the patient, clinical, and communication factors that are related to the provision of inappropriate treatment in the ICU and arrive at an empirical definition. The empirical definition will be validated and used to generate a model to prospectively identify patients at risk of receiving futile treatment. Understanding of the factors leading to provision of such care will advance the field by providing a foundation for intervention.


Jenny Shen, MD, MS
Assistant Professor
Division of Nephrology
LA BioMed/Harbor-UCLA

Project title: Racial and Ethnic Differences in the Initiation of Peritoneal Dialysis

Mentors:

Keith Norris, MD – UCLA
Gery Ryan, PhD – RAND
Sharon Adler, MD – LA BioMed/Harbor-UCLA

Multidisciplinary Expertise:
Nephrology, clinical outcomes, disparities research, health services research, pharmacoepidemiology

Project Description
Dialysis is a life-saving procedure for Americans with end-stage kidney disease. The most common modalities are hemodialysis (HD), which is generally performed in a dialysis unit by trained personnel, and peritoneal dialysis (PD), which is usually carried out at home by the patient. PD has been systematically underutilized in the U.S., particularly among black and Hispanic patients. This has significant implications since the modalities can affect patients’ lives quite differently. This project will explore racial and ethnic differences in the initiation of PD. We will first quantify the variation in PD use across racial and ethnic groups, then use qualitative research methods to explore why such variation exists. Finally, we will translate these results into a culturally competent group-based intervention that will educate patients about their modality choices. This will help ensure that patients of all racial and ethnic backgrounds have equal access to every type of dialysis care


2013 Awardees

Eliza Congdon, PhD
Assistant Professor
Department of Psychiatry & Biobehavioral Sciences
UCLA

Project title: Gene expression profiles of ECT response in Major Depressive Disorder

Mentors:

Nelson Freimer, MD – UCLA
Katherine Narr, PhD – UCLA
Randall Espinoza, MD, MPH – UCLA
Giovanni Coppola, MD – UCLA

Multidisciplinary Expertise:
Neurocognitive phenotyping, neuroimaging, neuropsychiatric genetics, gene expression, biopsychology

Project Description:
Dr. Congdon’s research project is aimed at identifying gene expression profiles of electroconvulsive therapy (ECT) response in patients with Major Depressive Disorder (MDD). Although there is evidence that neuromodulation induces changes in neurotrophic factors in brain regions implicated in MDD, and that peripheral gene expression is a useful surrogate for CNS activity in humans, there has been no investigation of the peripheral gene expression changes induced by ECT in MDD patients. Working with collaborators at UCLA, Dr. Congdon will leverage peripheral blood samples collected from MDD patients and matched controls enrolled in an ongoing neuroimaging study. She will test a neurotrophic hypothesis of MDD by identifying gene expression correlates of ECT response and risk of relapse in this sample of patients, and by integrating gene expression biomarkers with neuroimaging biomarkers. This research has the potential to delineate changes in gene regulation that underlie treatment response and risk of relapse in MDD.


Rebecca Dudovitz, MD, MSHS
Assistant Professor
Division of General Pediatrics
UCLA

Project title: Understanding the Relationship Between Adolescent Identity and Substance Use

Mentors:

Paul Chung, MD, MS – UCLA
Mitchell Wong, MD, PhD – UCLA
Gery Ryan, PhD – RAND
Chi-Hong Tseng, PhD – UCLA

Multidisciplinary Expertise:
General Pediatrics, School Health, Substance Use Prevention, Health Services Research

Project Description:
This project examines how self-concept, a potentially modifiable predictor of substance use, might be harnessed to prevent adolescent substance use. Using a mixed methods approach, we will first identify individual, family, peer and school-level predictors of healthy self-concept using cross-sectional survey data from 933 at-risk adolescents. In phase II, we will conduct semi-structured interviews with 40 high-risk adolescents to understand how different aspects of self-concept relate to substance use. We will use these findings to develop additional identity-related measures specific to risky health behaviors and examine their utility with current self-concept scales. In phase III, we make use of the first 3 waves of a longitudinal survey following 960 low-income adolescents from the end of 8th grade through the end of 10th grade to determine whether exposure to highly supportive schools impacts self-concept and whether changes in self-concept predict changes in substance use over time.


Heather Jones, MD
Assistant Clinical Professor
Division of Pulmonary/Critical Care Medicine
Cedars-Sinai Medical Center

Project title: Role of IL-1β and the NLRP3 Inflammasome in the Development of Hypoxemia in Acute Lung Injury

Mentors:

Moshe Arditi, MD – Cedars-Sinai Medical Center
Paul Noble, MD – Cedars-Sinai Medical Center

Multidisciplinary Expertise:
Pulmonology, Critical Care, Immunology

Project Description:
Acute Respiratory Distress Syndrome (ARDS) is a clinical syndrome of acute lung injury and failure characterized by a sudden onset and a profound inability of the lungs to oxygenate the blood (hypoxemia). ARDS has a mortality rate of 30% and is responsible for 75,000 deaths annually in the United States. Despite several decades of research, we still do not understand why ARDS develops and no treatments have been found. Interleukin 1β (IL-1B) is a potent pro-inflammatory cytokine that is implicated in the pathogenesis of ARDS; its secretion is regulated an intracellular complex termed the NLRP3 inflammasome. Our preliminary data in a mouse model suggests a novel role for the NLRP3 inflammasome and IL-1B specifically in the severe hypoxemia seen in ARDS. The purpose of this investigation is to elucidate the mechanism for IL-1B?dependent hypoxemia in ARDS.


David Merrill, MD, PhD
Assistant Professor
Division of Geriatric Psychiatry
UCLA

Project title: Relationship of physical activity to hippocampal structure and memory in MCI

Mentors:

Gary Small, MD, MS – UCLA
Susan Bookheimer, MD, PhD – UCLA
Bruce Dobkin, MD – UCLA

Multidisciplinary Expertise:
Geriatric psychiatry, dementia, neuroscience, neuroimaging

Project Description:
This observational study aims to examine the effects of physical activity levels on hippocampal structure and memory in older adults with mild cognitive impairment (MCI). Volunteers will have their physical activity monitored for two weeks at a time over a year and a half. Dr. Merrill will test memory and measure hippocampal structure at the beginning of the study and again 18-months later using neuropsychological testing and high resolution magnetic resonance imaging (MRI) to understand the relationship of these factors to physical activity levels in MCI volunteers. Dr. Merrill will also measure potentially related factors such as vascular health, family history of dementia, APO-E genotypes, etc., both to control for these potential confounds and to examine any interactive effects of these variables. This paradigm will establish a methodology within which to then test lifestyle interventions in populations at risk of developing Alzheimer’s disease and related dementias.


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Michael Shino, MD, MSCR
Clinical Instructor
Division of Pulmonary and Critical Care Medicine
UCLA

Project title: Mechanisms of allograft injury and the development of bronchiolitis obliterans syndrome after lung transplantation

Mentors:

John Belperio, MD - UCLA
Robert Elashoff, PhD – UCLA
Elaine Reed, PhD - UCLA

Multidisciplinary Expertise:
Lung transplantation, acute lung injury, immunology, immune monitoring, chemokine analysis

Project Description:
Chronic rejection or bronchiolitis obliterans syndrome (BOS) is the major factor limiting long-term survival after lung transplantation (LT). The pathogenesis of BOS remains unknown with no effective treatments. Thus, the identification and avoidance of BOS risk factors is critical.  Prior studies of BOS have traditionally focused on the effects of individual “insults” (e.g., infection, acute rejection, ischemia-reperfusion,  gastroesophageal reflux) to the allograft. In contrast, this project will investigate the association between allograft "injury" and the development of BOS. Our preliminary data suggests that the histopathologic patterns of allograft injury are much stronger determinants of BOS development than the various insults causing them. Furthermore, we find that this association may be mediated by an aberrant Type I immune response involving CXCR3/ligands. Gaining a better understanding of the risk factors and mechanisms responsible for BOS development will lead to novel ways to predict, prevent and treat this devastating syndrome.


Joshua Pevnick, MD, MSHS
Assistant Professor
Department of Biomedical Sciences
Cedars-Sinai Medical Center

Project title: Minimizing Errors in Medication Histories Obtained at Hospital Admission

Mentors:

Douglas Bell, MD, PhD – UCLA
Cynthia Jackevicius, PharmD, MSc – VA Greater Los Angeles Healthcare System
Andre Rogatko, PhD – Cedars-Sinai Medical Center
Rita Shane, MD – Cedars-Sinai Medical Center

Multidisciplinary Expertise:
Health services research, clinical informatics, hospital medicine, clinical trials, medication management

Project Description:
Dr. Pevnick will study three interventions to improve the accuracy of medication histories obtained at hospital admission. The interventions will target elderly and chronically ill patients prone to erroneous medication histories and resultant medication errors. For targeted patients, Dr. Pevnick will test the effect of using pharmacists and pharmacy technicians to obtain an initial medication history. He will also study the potential benefit of accessing electronic claims data at the time of admission to improve medication history accuracy. This project holds promise for understanding how best to apply three promising, emerging interventions to improve medication history accuracy. Improving the accuracy of admission medication histories is accepted as a necessary first step in preventing adverse drug events, which cause over 100,000 deaths in hospitalized patients annually. Beyond studying potential solutions to this public health threat, the proposed research will help to develop Dr. Pevnick into an independent investigator.


Anne Walling, MD, PhD
Assistant Professor
Division of General Internal Medicine &Health Services Research
UCLA

Project title: Single Fraction vs. Multiple Fraction Radiation for Patients with Advanced Cancer and Painful Bone Metastases

Mentors:

Neil Wenger, MD, MPH – UCLA
Michael Ong, MD, PhD – UCLA
Michael Steinberg, MD – UCLA

Multidisciplinary Expertise:
Palliative Care, Radiation Oncology, Ethics, Health Services Research

Project Description:
One example of a quality gap that has been identified by recent studies of supportive cancer care quality is the high rate of multiple fraction (compared to single fraction) palliative radiation for patients with advanced cancer and painful bone metastasis despite evidence suggesting that there are similar pain outcomes and that the burden of multiple treatments may impact quality of life negatively. The goal of this career development award is to use quantitative and qualitative methods to evaluate current practice and develop an intervention to improve radiation oncology practice that translates the best evidence from clinical trials into practice. A successful intervention aims to improve quality of life and satisfaction for a particularly vulnerable patient population while potentially decreasing healthcare costs.


Piwen Wang, MD, PhD, MS
Assistant Professor
Division of Cancer Research and Training
Department of Internal Medicine
Charles R. Drew University of Medicine and Science

Project title: Sensitization of castration-resistant prostate tumors to docetaxel treatment by green tea and quercetin

Mentors:

Jaydutt Vadgama, PhD – Charles R. Drew University of Medicine and Science
Susanne Henning, PhD, RD – UCLA
David Heber, MD, PhD – UCLA

Multidisciplinary Expertise:
Translational nutrition and cancer research, Oncology, Toxicology, Biostatistics

Project Description:
Chemotherapy with docetaxel (Doc), a cell division inhibitor, is a standard treatment for metastatic and castration-resistant prostate cancer (CRPC). However, acquired resistance to Doc develops early in most patients. My project is designed to elucidate the molecular mechanisms of Doc resistance and to determine whether natural products green tea (GT) and quercetin (Q) will reverse the chemoresistance and enhance the efficacy of Doc. Both GT and Q selectively inhibit cell proliferation, induce cell cycle arrest and apoptosis in prostate cancer cells without affecting normal cells. Combined treatment with GT and Q enhanced the antiproliferative effect of Doc 5-fold in cultured castration-resistant prostate cancer cells, associated with increased apoptosis, cell cycle arrest and decreased multidrug resistance protein expression. The proposed mouse study will test the combined effect in vivo. This project will set the stage for future clinical trials to enhance drug efficacy at lower doses and reduce side effects.

2012 Awardees


McKinnell,_James.jpgJames A. McKinnell, MD

Assistant Professor of Medicine

LA BioMed/Harbor-UCLA


Project title:
Using Research in Vancomycin-Resistant Enterococcus to Validate an Efficient System of Quantifying Antibiotic Utilization

Mentors:

Loren G. Miller, MD, MPH – LA BioMed/Harbor-UCLA

Susan S. Huang, MD, MPH – UC Irvine

Martin F. Shapiro, MD, PhD – UCLA

Multidisciplinary Expertise:
Infectious Disease, Health Services Research, Clinical Trials, and Clinical Outcomes Research

Project Description:
Approximately 100,000 Americans die every year from infections acquired in hospitals. HAI due to Vancomycin-resistant Enterococcus spp. (VRE) are of particular concern. VRE HAI’s disproportionately affect the most immunocompromised hosts, such as organ transplant recipients, and the severely immunosuppressed. Each VRE bloodstream infection (VRE-BSI) is associated with $50,000 of additional healthcare costs and a 35% attributable mortality. The purpose of this investigation is to 1) evaluate the association between antibiotic use and VRE-BSI incidence, 2) investigate VRE-BSI outcomes using improved methodologies, and 3) validate an electronic source of patient-level antibiotic usage data that can be used for investigations of VRE-BSI and further research on other important pathogens.

Dr. McKinnell will work to develop a database to evaluate the association between antibiotic use, VRE-BSI incidence, and outcomes of patients with VRE-BSI from data derived from Ronald Reagan Medical Center. He will also lead efforts to conduct a retrospective chart review to define the predictors of treatment success among hospitalized patients with VRE-BSI and validate the antibiotic database.


Mary E. Sehl

Mary E. Sehl, MD, PhD

Assistant Clinical Professor of Medicine

Division of Hematology-Oncology, UCLA


Project title: Modeling of EMT/MET transitions in breast cancer stem cells

Mentors:

Kenneth Lange, Ph.D. - UCLA

Gay Crooks, M.B.B.S. - UCLA

Max Wicha, M.D. – University of Michigan

Multidisciplinary Expertise:
biomathematics, oncology, cancer stem cells

Project description:
Breast cancer is the most common type of cancer diagnosis in women, with the majority of deaths caused by distant recurrence.

Stem cell-targeted therapies offer new hope in eradicating breast cancer stem-like cells that lead to recurrence after standard therapies fail. Mathematical models have proven useful in studying the population dynamics of cancer stem cells under targeted therapy and are informative in assessing safety and duration of therapy. However, the complexities of the stem cell microenvironment limit the predictive ability of analytic models and suggest the necessity of more informed modeling strategies.

Stochastic simulation methods model rare events that are important in cancer modeling, such as extinction and mutation, and have the ability to address complex dynamics and incorporate feedback of reaction networks in systems biology.  We postulate a model in which breast cancer stem-like cells freely convert between an epithelial (proliferative) and mesenchymal (quiescent, invasive) state, through epithelial-to-mesenchymal transition (EMT) and the reverse process (MET). The mesenchymal state is identified by CD44, a marker of cell adhesion and invasive potential, while epithelial stem cells can be CD44 negative and express ALDH, a marker of mammary stem cells and predictor of poor clinical outcome (6). Cytokines such as IL-6 and TGF-beta, as well as intracellular signaling and miRNAs, may regulate the interconversion of breast cancer stem-like cells between EMT-like and MET-like states. 

We propose a combination of theoretical modeling with experimental validation to study the rates and regulators of EMT/MET transitions in breast cancer stem-like cells. We apply our model to predict alterations in stem cell populations and their regulatory pathways in response to niche-targeted therapy. Ultimately, predictions of therapeutic efficacy and safety could be validated in clinical trials and used to guide drug development and plan therapy duration. We envision that extinction models will provide a novel approach to therapeutic design.


David ShackelfordDavid Shackelford, PhD

Assistant Professor of Medicine

Division of Pulmonary and Critical Care Medicine, UCLA

Project title: Development of novel therapeutic strategies to target LKB1/STK11 deficient non-small cell lung cancer

Mentors:

Steven M. Dubinett, MD – UCLA

Hong Wu, MD, PhD – UCLA

Multidisciplinary Expertise:
Translational cancer research, signal transduction, metabolism, lung carcinogenesis, genetically engineered mouse models of lung cancer, micro PET-CT imaging

Project Description:
My project focuses on identifying and testing novel therapies for the treatment of early stage LKB1-deficient lung tumors. The LKB1 tumor suppressor functions as a master regulator of cellular growth, metabolism and survival.  Importantly, the LKB1 gene is frequently mutated in ~35% of non-small cell lung cancer (NSCLC) however, the molecular mechanisms driving tumor growth following LKB1 mutations are poorly understood and to date there are no therapies that target LKB1-deficient lung cancer.  As more targeted therapeutics for NSCLC are needed, I explored use of biguanides, traditionally used to treat diabetes, as metabolic stress agents to target LKB1-deficient lung tumors.  At a cellular level, LKB1-deficient tumor cells are unable to respond to energy stress and selectively undergo increased apoptosis following treatment with metabolic stress agents such as biguanides. The selective sensitivity of LKB1-deficient tumors to metabolic stress presents an Achilles heel to exploit and opens a therapeutic window from which to target LKB1-deficient cells. Additionally, loss of the LKB1 gene results in elevated mTOR signaling that results in increased tumor growth and proliferation.  My project will investigate the use of biguanides (metformin or phenformin) in combination with targeted mTORC1 inhibitors (rapamycin or INK128) for the treatment of LKB1-deficient NSCLC.  I will perform preclinical studies using genetically engineered mouse models of lung cancer to assess the efficacy these novel drug combinations in vivo.  Using micro 18FDG-PET and bioluminescence imaging in combination with detailed immunohistochemical and biochemical analysis I will dissect the molecular signaling pathways driving tumor growth and survival in LKB1-deficient lung tumors. With this multifaceted approach I aim to uncover novel pathways that can be exploited therapeutically in LKB1-deficient tumors. My overarching goal is to identify new, clinically relevant therapeutic strategies to treat patients with NSCLC harboring LKB1 mutations.

2011 Awardees

UCLA CTSI awarded its first KL2 awards in November, 2011. Our scholars were selected from a pool of 28 outstanding candidates—10 from basic science, 11 from clinical research and seven from health services research.

Profiles of our KL2 Translational Science Scholars follow.

2011 Translational Science Scholars

Amira K. Brown, PhD

Assistant Professor
Department of Internal Medicine
Charles R. Drew University of Medicine and Science
Project: Effects of varenicline on alcohol and nicotine consumption and changes in dopamine d2-like receptor availability in high-alcohol-preferring mice

Mentors:

Theodore Friedman, MD, PhD - Charles R. Drew University of Medicine and Science

Mark Mandelkern, MD, PhD - VA Greater Los Angeles Health System

Multidisciplinary Expertise:
Endocrinology, Medical Physics, Pharmacology, Psychology

Project Description:
Dopamine is a chemical in the brain with many important functions. This project aims to understand the role of the dopamine receptor system in concomitant alcohol and nicotine abuse and treatment.

The project specifically focuses on the d2 dopamine receptor, which is involved in reward-seeking behavior. Lower d2 dopamine receptors have been shown in animal models of addiction and substance abusers.

Positron emission tomography (PET) will be used to characterize the dopamine d2 receptor profile in the brains of high-alcohol-preferring (HAP) and low-alcohol-preferring (LAP) mice. We expect that HAP mice will have significantly lower dopamine d2 receptor availability in an area of the brain called the striatum when compared to LAP or normal, wild-type mice.

This study also will examine the effects of varenicline, a smoking-cessation drug, on dopamine d2 receptor availability, nicotine and alcohol consumption in HAP and LAP mice. HAP mice will increase their voluntary alcohol consumption following chronic nicotine exposure; that increase will be related to decreases in striatal d2 receptor availability. However, following varenilcine treatment, HAP mice exposed to chronic nicotine are expected to decrease their voluntary intake of alcohol; that decrease in alcohol intake will be related to increases in dopamine d2 receptor availability.

Results from this study will provide important scientific and clinical information regarding the role of the dopamine receptor system in the underlying mechanisms of comorbid alcohol and nicotine preference. Moreover, finding an effective pharmacotherapy for this addiction is crucial; as such, the project will determine whether changes in dopamine receptors are involved in the efficacy of varenicline treatment success.



Joshua J. Zaritsky, MD, PhD

Assistant Professor
Pediatrics Division of Pediatric Nephrology
Mattel Children's Hospital, UCLA
Project: Hepcidin and the anemia of chronic kidney disease

Mentors:

Isidro Salusky, MD - UCLA

Tomas Ganz, MD, PhD - UCLA

Kamyar Kalantar-Zadeh, MD, MPH, PhD - LA BioMed/Harbor-UCLA Medical Center

Multidisciplinary Expertise:
Nephrology, Pediatrics

Project Description:
Erythropoiesis-stimulating agents (ESA)(drugs used to spur red blood cell production), are an important component of anemia therapy in patients with chronic kidney disease (CKD). ESA hyporesponsiveness, however, occurs frequently and is often associated with iron deficiency and inflammation as well as poor outcomes. Given the urgent need to explore novel approaches that can allow ESA dose reduction as recently recommended by the FDA, it is crucial to understand the molecular mechanisms that link inflammation, iron balance and erythropoiesis in CKD. Hepcidin, a protein produced in the liver, is a key regulator of iron homeostasis. Preliminary data indicates that hepcidin accumulates in CKD, making it likely that hepcidin plays a major role in the anemia of CKD as well as ESA hyporesponsiveness.

This project aims to expand our knowledge of hepcidin biology in the setting of CKD. It will examine two hypotheses: (1) Does progressive loss of kidney function directly lead to increased hepcidin levels? and (2) Do these increased hepcidin levels contribute to iron restriction and anemia in experimental animals with CKD?

This project will provide crucial knowledge as to whether hepcidin contributes to the anemia of renal disease and ESA hyporesponsiveness and thus will help to optimize anemia treatment of CKD.



Gelareh Z. Gabayan, MD, MSHS

Assistant Professor
Medicine/Emergency Medicine
David Geffen School of Medicine
UCLA VA Greater Los Angeles Health System
Project: Patterns and predictors of poor outcomes following emergency department discharge in older adults

Mentors:

Catherine A. Sarkisian, MD, MSPH - UCLA

Arthur Kellermann, MD, MPH - RAND

Jerome R. Hoffman, MD, MA - USC

Multidisciplinary Expertise:
Emergency Medicine, Geriatrics, Health Services Research

Project Description:
This project assesses Emergency Department (ED) quality and patient safety by evaluating the factors associated with poor outcomes following an ED visit. In collaboration with Kaiser Permanente Southern California and using a case-control study design, this study will identify the patterns and predictors of short-term mortality or an ICU admission following discharge from the ED in older adults. The ultimate goal of this project is to reduce the incidence of preventable poor outcomes following discharge from the ED through the implementation of feasible and practical Emergency Department systems-based interventions.

Can candidates applying for a CTSA KL2 appointment also apply for additional mentored K awards?

The trans-NIH policy stipulates that K12 candidates may not apply or have pending an application for a similar mentored K awards simultaneously.

Are postdoctoral research fellows eligible to apply for the KL2 award?

Yes, as long as the applicant has a full-time junior faculty appointment at one of the partner institution by July 1st of the application year.

What is the application cycle of the KL2 program?

The KL2 application runs on an annual cycle (timeline is subject to change).
     Pre-Application Deadline  Early December
     Pre-Application Feedback & Decisions  Mid December
     Full Application Deadline  Late February
     Interview Notifications  Late April
     Selected Candidate Interviews  Early to mid May
     Award Notifications  End of May to early June
     Grant Start Date  July 1

Is the July 1st start date flexible?

No.

Does the primary mentor need to be from one of the partner institutions (Cedars, CDU, LA BioMed-Harbor, UCLA?

It's not a requirement. However, the applicant should realize that it tends to be difficult for individuals to get strong mentorship when the mentor is at another institution. It would probably be better if the applicant had a mentor at their home institution as well.

The website and RFA both indicate the KL2 is for junior faculty to conduct patient-oriented research. Does this mean that the project needs to have direct patient contact?

No. The KL2 award is opened to applications from basic science, clinical research and health services research, which include a translational research plan.

Can an applicant have a VA Career Development Grant that is over $100,000 in direct costs?

No. Applicants cannot be or have been a PI on an equivalent non-PHS peer reviewed research grant that is over $100,000 in direct costs per year.

Can an applicant be on a J-1 Visa as part of the Exchange Visitor Program?

No. Applicants must be a citizen or non-citizen national of the United States, or be lawfully admitted to the United States for permanent residence

I do not have my junior faculty appointment yet, how does that play out when applying for the award?

A junior faculty appointment is required. If your junior faculty application is "in process," please make sure this is stated in the letter of support from your department chair or division chief.

What is the format for the budget and budget justification?

Per the KL2 instructions, please submit the budget and justification in NIH format. You can find the forms here through this website: http://grants.nih.gov/grants/funding/phs398/phs398.html. Form Page 4 is generally used to prepare the budget proposal for each year of the KL2 and the justifications can go on the "Continuation Format Page."

Is the Other Support Pages only asking for information on NIH grants? If not, can you spell out exactly what is needed? (e.g. types of grants/contracts for which paperwork is needed, and exactly what paperwork is needed).

We are requesting Other Support Pages from application on their current, past and pending grants. The OS Pages should follow the NIH guidelines: Other Support includes all financial resources, whether Federal, non-Federal, commercial or institutional, available in direct support of an individual's research endeavors, including but not limited to research grants, cooperative agreements, contracts, and/or institutional awards. Here is a link the NIH Other Support Pages form: https://grants.nih.gov/grants/forms/othersupport.htm

The instructions state "Please note that the education plan is worth 1/4 of the final score and should be tightly integrated with the research plan." Is there a breakdown somewhere explaining how much each part of the application is worth?

The review committee will be looking at: (1) candidate, (2) research plan, (3) educational plan, and (4) mentor/institutional support. Each criterion will account for 1/4 of your total score.

How can I enroll in UCLA courses through UCLA Extension?

Click here for information on how to enroll in UCLA courses through UCLA Extension.

Do I need to be currently appointed at UCLA to apply for the KL2 Program?

Applicants may apply from another institution as long as they will be appointed at UCLA by their starte date. The institutional letter should note that the applicant will be appointed at UCLA by July 1st of the application year.

Can I choose any mentor or is there a list of KL2 mentors to choose from?

You are expected to choose your own primary mentor.

I would like to apply for the KL2 Translational Science Award and am writing to see if my research would be consistent with that of the program.

Although I cannot tell you specifically whether your research would be consistent with our program... the proposed projects we have received range from basic science, clinical research and health services research. Questions regarding your research plan should be directed to your primary mentor.

I am applying for the KL2 from UCLA, does the application need to go through OCGA?

No.

Should the research proposal and budget be planned for one year or three years?

The budget and proposal should reflect the plan for the entire 3 years.

From where can I get my NIH Other Support Pages?

Please check with your department or division's fund managers.

I have included a brief description of my research plan. Can you review it to make sure it is feasible for the KL2?

Unfortunately we are unable to provide you guidance on the content, structure, and strategy. These questions should be directed to your primary mentor.

Are there any successful K12/KL2 grant applications for clinical research that you can share with me?

I can't share the applications with you.

Do you have any budget guidelines and examples that I can refer to?

Sample budgets cannot be released from past applicants. The budgets and justifications should be submitted on a detailed NIH-formatted form: http://grants.nih.gov/grants/funding/phs398/phs398.html. The budgets and justifications should show how you plan to spend these funds. Awardees will receive salary support to $75,000 a year for 75% effort. This does not include benefits, which should be calculated separately. The award also provides annual amounts of $25,000 for research, $4,000 for tuition and career development, $2,000 for travel, and $1,500 for statistical support.

I'd like to hire a half-time research coordinator dedicated solely to my project, would that be covered under the research budget? Could a portion of my salary be used to cover the research coordinator's budget?

The salary support of up to $75,000 is only for the awarded Scholar. Your research coordinator salary would need to go under the research budget.
The K Bridge Program is specifically intended to help junior faculty who have submitted a NIH K award grant (mentored career development scientist award) and have received competitive scores on their proposal. This funding will support the faculty member and provide additional time for productivity as they strengthen their proposal for resubmission.

2018 Awardees

Alexandra Binde

Alexandra Binder, ScD, MS
Assistant Professor-in-Residence
Department of Epidemiology
UCLA

Project title: Interaction between reproductive and epigenetic aging on breast cancer risk

Mentors:

Steve Horvath, PhD, ScD – UCLA
Andrea LaCroix, PhD – UCSD
Roshan Bastani, PhD – UCLA
Patricia Ganz, MD – UCLA

Multidisciplinary Expertise:
Multidisciplinary Expertise: Epigenetic regulation, aging, women’s health, breast cancer, epidemiology, biostatistics

Project Description:
Biological age is a modifiable predictor of health influenced by behaviors and exposures across the life course. Epigenetic modifications can provide a cellular memory of these forces, and program long-term physiological alterations through stable shifts in gene regulation. Accordingly, specific patterns of epigenetic variation have been used to predict biological age (i.e. epigenetic age). Accelerated epigenetic age relative to chronological age (AgeAccel) has been robustly associated with increased total cancer risk and all-cause mortality. We postulate that a comprehensive understanding of the predictors of AgeAccel, including its connection to the reproductive aging process, has the capacity to improve postmenopausal breast cancer risk prediction models. We plan to characterize the association between AgeAccel and reproductive history, endogenous hormone levels, and health behaviors. Based on these systematic analyses, we will appraise the ability of AgeAccel to identify women at high risk for postmenopausal breast cancer more accurately than currently known risk factors.


2016 Awardees

Alison Chu

Alison Chu, MD
Assistant Professor
Division of Neonatology
UCLA

Project title: The role of IL10 in early vascularity and endothelial dysfunction, and programming of adult cardiovascular disease

Mentors:

Sherin Devaskar, MD - UCLA
Madhuri Wadehra, PhD - UCLA

Multidisciplinary Expertise:
Placenta, immunology of reproduction, endothelial dysfunction, vasculogenesis, intrauterine growth restriction

Project Description:
Placental insufficiency encompasses a spectrum of pregnancy disorders including pre-eclampsia, recurrent miscarriage, and intrauterine growth restriction (IUGR). Its pathophysiology is poorly understood and there is a lack of validated prevention strategies, diagnostic testing, and treatment for placental insufficiency. My project focuses on altered placental vascularization in IUGR, and proposes to study how: (1) altered placental vascularization, as mediated via immunologic regulatory inputs, leads to placental insufficiency, and (2) endothelial dysfunction is programmed by in utero environment, leading to adverse adult cardiovascular outcomes. These objectives will be accomplished by using human placental samples, animal models of IUGR, and endothelial cell lines to establish mechanistic relationships. Placental insufficiency and its associated disorders represent a significant public health burden, as it puts both mothers and offspring at increased risk for short-term and long-term complications, and this project could better our understanding of pathophysiology, leading to biomarkers of disease and/or therapeutic targets.


Jennifer Fulcher

Jennifer Fulcher, MD, PhD
Assistant Professor-in-Residence
Division of Infectious Diseases
UCLA

Project title: Mucosal Innate Immunity and Pathogenesis of HIV-1 Transmission

Mentors:

Otto Yang, MD - UCLA
Peter Anton, MD - UCLA

Multidisciplinary Expertise:
Infectious diseases, mucosal immunology, innate immunity

Project Description:
Mucosal HIV-1 transmission accounts for the majority of new HIV infections, yet is a poorly understood event. Risk of HIV acquisition varies, and there are individuals who remain uninfected despite repeated high-risk exposures, termed HIV-exposed seronegative (HESN). It is known that immune activation and inflammation can facilitate HIV-1 mucosal transmission, therefore, we hypothesized that altered immune reactivity may contribute to differences in HIV susceptibility. To test this, the susceptibility and reactivity of the mucosal innate immune system will be assessed in HESN compared to healthy control individuals using ex vivo infectibility assays with freshly-acquired mucosal biopsies, examination of mucosal immune responses to defined stimuli, and characterization of innate immune cell types in these tissues. Collectively these data will help define the influence of innate immune stimulation on HIV-1 infection and replication, which could lead to new targets for prevention therapeutics.


Jennifer Fulcher

Jon Sin, PhD
Postdoctoral Scientist
Department of Medicine, Heart Institute
Cedars-Sinai Medical Center

Project title: Coxsackievirus B subverts host mitophagy to promote viral dissemination and myocarditis

Mentors:

Roberta A Gottlieb, MD – Cedars-Sinai Medical Center
Moshe Arditi, MD - Cedars-Sinai Medical Center

Multidisciplinary Expertise:
Virology, cardiovascular biology, mitochondrial biology, stem cell biology

Project Description:
Coxsackievirus B (CVB) is a common pathogen that can cause a wide-array of inflammatory diseases including meningitis, pancreatitis, and myocarditis. We see that CVB which is a naked virus can escape the cell in membrane-bound vesicles which we hypothesize are derived from autophagosomes. Additionally, when we infect HL-1 cardiomyocytes, mitochondrial networks fragment, which is an early step in the autophagic degradation of mitochondria (mitophagy). Normally, the E3 ubiquitin ligase parkin would subsequently ubiquitinate these fragmented mitochondria to target them for destruction; however, we find that following mitochondrial fission, instead of getting degraded mitochondrial fragments and virus are ejected from the cell in membrane-bound vesicles. We found that treating cells with DRP1-inhibitor Mdivi-1 prior to infection results in reduced intracellular and extracellular virus, suggesting that blocking the early steps in mitophagy suppresses viral dissemination. We will test the efficacy of Mdivi-1 in suppressing CVB-mediated myocarditis in mice.


2015 Awardees

Pamela K. Douglas

Pamela K. Douglas, PhD
Klingenstein Third Generation Fellow
Department of Psychiatry & Biobehavioral Sciences
UCLA

Project title: Translating Archetypal ADHD Neuroimaging Clusters for Diagnosis

Mentors:

Susan Bookheimer, PhD - UCLA
James McGough, MD - UCLA
Andrea Bertozzi, PhD, MA – UCLA
Paul Thompson, PhD – USC

Multidisciplinary Expertise:
Functional MRI, multimodal neuroimaging, machine learning, dynamic systems modeling, ADHD

Project Description:
ADHD is a highly heritable (60-75%) child-onset neurodevelopmental disorder with an economic burden to society estimated to be in the tens of billions per year. Behaviorally, ADHD is characterized by problems with sustained attention and hyperactivity/impulsivity that often impair academic, social, and occupational abilities. The negative consequences put children with ADHD at greater risk for anxiety and depression, and adolescents with ADHD are at greater risk for automobile accidents, nicotine dependency and drug experimentation. Nonetheless, the neural underpinnings of the disease remain unknown, and there is tremendous variation in response to drug treatment. Here, we will study brain symmetry in structural MRI biomarkers of ADHD – a new approach - and integrate structural-functional knowledge with clinical characteristic of ADHD using state-of-the-art mathematical algorithms on two “big data” sets. The goal is to translate these findings into the clinical setting, and track these measures longitudinally over the course of medical intervention.


Bergen Nelson

Bergen Nelson, MD, MS
Assistant Clinical Professor
Division of General Pediatrics
UCLA

Project title: Developing Tiered Care Pathways for Young Children with Developmental Risks

Mentors:

Paul Chung, MD, MS— UCLA
Neal Halfon, MD— UCLA
Moira Inkelas, PhD— UCLA
Ning Li, PhD— UCLA
Frederick Zimmerman, PhD – UCLA
Frances Glascoe, PhD—Vanderbilt University
Paul Shekelle, MD, PhD—RAND Corporation

Multidisciplinary Expertise:
Early childhood development, developmental screening, longitudinal data analysis, risk prediction models, clinical quality improvement and implementation science

Project Description:
Child health providers are encouraged to conduct early childhood developmental screening and surveillance as the primary way to identify the 5-10% of young children with developmental disabilities. In addition, however, an estimated 30% of children under 5 years old have developmental and behavioral risks which place them on worse trajectories in terms of long-term developmental, educational, and health outcomes. This project will develop a risk prediction model for poor school readiness at kindergarten entry, among children without developmental delay at age 2, using an existing longitudinal dataset. We will then translate the findings from these secondary data analyses into a clinically useful risk prediction and decision support tool, to identify children at high risk and connect them with effective support services in the community.


Nava Yeganeh

Nava Yeganeh, MD, MPH
Visiting Assistant Professor
Division of Pediatric Infectious Diseases
UCLA

Project title: Including Men to Prevent Prenatal Infections in Infants: the TRIPAI Initiative

Mentors:

Karin Nielsen, MD, MPH – UCLA
David Elashoff, PhD – UCLA
Pamina Gorbach, DrPH – UCLA
Jeffrey Klausner, MD - UCLA

Multidisciplinary Expertise:
Prevention of mother to child transmission of HIV, sexually transmitted diseases, partner testing, Point of Care testing

Project Description:
Maternal acquisition of sexually transmitted infections (STIs) and vaccine preventable diseases during pregnancy could lead to poor health outcomes in both the mother and the infant. Women are at higher risk for acquiring STIs including HIV during pregnancy for both biological reasons such as physiological immunosuppression as well as behavioral ones such as decreased condom use. Prior research at our site in Porto Alegre, Brazil shows that approximately half of male partners are willing to attend prenatal care to receive point of care testing for HIV, and if infected, are successfully entered into treatment to avoid transmission to pregnant woman and infants. Our aim in this new phase is to use mixed methods to better involve fathers in prenatal care in order to screen and treat them for various STIs and vaccine preventable diseases. With early diagnosis, counseling and treatment, we hope to decrease the rates of preventable congenital and neonatal infections.

2013 Awardees

Guerrero,_Alma.jpg

Alma Guerrero, MD, MPH
Assistant Professor
Department of Pediatrics
UCLA

Project title: Preventing Childhood Obesity: Addressing the Family Environmental Factors

Mentors:

Deborah Glik, ScD – UCLA
Wendy Slusser, MD - UCLA
Paul Chung, MD, MS - UCLA
Thomas Belin, PhD - UCLA

Multidisciplinary Expertise:
General Pediatrics, Latino Children's Health, Childhood Obesity, Early Childhood, Child Development

Project Description:
My K23 Mentored Career Development Award will focus on a sequential mixed methods research approach to address childhood obesity prevention. A family-focused intervention will be developed to prevent childhood obesity based on formative qualitative research, components of an evidence-based parent training intervention, and the dietary and physical activity practices consistent with the American Academy of Pediatrics guidelines. The intervention will be piloted and preliminary outcomes as well as the feasibility, acceptability, and sustainability of the intervention will be examined. The K23 Award will support the necessary coursework, mentorship, and experiential learning in community-based participatory research, the design and implementation of intervention studies, analysis of longitudinal data, and dissemination science to become an expert in community-based interventions to address early childhood obesity.


Marcus,_Elizabeth.jpg

Elizabeth Marcus, MD
Assistant Clinical Professor
Division of Pediatrics Gastroenterology
UCLA

Project title: Mechanisms of gastric mucosal response to H. pylori infection at acidic pH

Mentors:

George Sachs, MD – UCLA
Charalabos Pothoulakis, MD - UCLA
David R. Scott, PhD - UCLA
Julian P. Whitelegge, PhD - UCLA

Multidisciplinary Expertise:
Pediatric Gastroenterology, intestinal failure, intestinal transplant, Helicobacter pylori infection, physiology and membrane biology

Project Description:
H. pylori infects 50% of the world’s population and causes gastritis, gastric and duodenal ulcer disease, and gastric cancer. Infection often occurs early in life and remains lifelong without treatment. All infected develop gastritis, and it is unknown why some individuals progress to develop advanced disease. H. pylori lives in an acidic environment at the site of infection, the human gastric mucosa. The aim of this work is to establish model systems that mimic the gastric environment by using gastric cells that form a true epithelium in the setting of physiologic acidity to study host response to infection. Acidity will be modulated in an in vivo gerbil model as well. The goal is to determine factors relevant for progression to advanced disease, which will help improve treatment and decrease incidence of ulcer disease and gastric cancer.


Payne,_Laura.jpg

Laura Payne, PhD
Adjunct Assistant Professor
Pediatric Pain Program
UCLA

Project title: Central Pain Mechanisms in Primary Dysmenorrhea

Mentors:

Lonnie Zeltzer, MD - UCLA
Andrea Rapkin, MD - UCLA
Bruce Naliboff, PhD - UCLA

Multidisciplinary Expertise:
Chronic pain, adolescent and women’s health, psychophysiology, neuroendocrinology, psychology

Project Description:
This primary goal of this research is to evaluate differences in central excitatory and inhibitory pain modulation in young women with and without primary dysmenorrhea (PD). The project involves comparing adolescent and young adult girls (ages 16-21) with and without PD during each of 3 phases of the menstrual cycle (menstruation, ovulatory, luteal) across a variety of standardized experimental pain testing paradigms designed to evaluate pain sensitivity and central excitatory and inhibitory mechanisms. In addition, differences in autonomic nervous system (ANS) and hypothalamic-pituitary axis (HPA) responses, as well as how psychological factors (depression, anxiety, and emotion regulation) influence pain, will be explored. This study is the first of its kind to explore pain responses in PD across the developmental spectrum, which has the potential to identify individuals at risk for the development of future chronic pain problems and inform new interventions and prevention strategies.

About

The K Scholars Society, managed by the UCLA CTSI’s KL2 Program, supports the career development of junior investigators building careers in clinical and translational research. This program is designed for scholars within the UCLA CTSI partner institutions who have current career developments awards from the National Institutes of Health (e.g. K01, K08, K23, K99/R00), or equivalent awards from other federal (e.g. DOD, VA) and non-federal (e.g. AHA, ACS, Doris Duke) funding agencies.

Eligibility Requirements and Registration

ELIGIBILITY

  • Be an investigator from one of the UCLA CTSI institutions (Cedars-Sinai, CDU, Harbor-UCLA, and UCLA Westwood).
  • Have a current NIH K or equivalent other federal (e.g. DOD) or foundation (e.g. AHA, Doris Duke) career development award. You will be asked to supply grant information and the Notice of Award (for non-NIH grants) in the registration form.
  • Must be able to complete the two-year curriculum.
Registration for the 2019-21 program is closed.  Please check back during Spring 2020 to register for the 2020-22 program.

Curriculum and Program Resources

TWO-YEAR CURRICULUM ACTIVITIES

These monthly meetings generally take place on the 3rd Tuesday of each month from 3:00-5:00 pm unless otherwise noted. Ad hoc sessions are also scheduled as needed.

  • Monthly Didactic Seminars (1 hr): grant writing, communication, storytelling, presentation skills, team science, career strategy, entrepreneurship, mentorship, and leadership trainings.
  • Monthly Work-in-Progress Sessions (1 hr): Investigators will have the opportunity to present their work in progress to a diverse group of scholars and faculty.
  • Priority for Grant Writing Studios: These are individually tailored to each scholar for longitudinal mentoring on NIH K and R grant submissions. Studios are comprised of a panel of 3-4 mentors (scientific, career and statistics) with expertise in K and/or R grant development. The panel meets with the scholar 2-3 times from the concept phase to final product. The scholar will then participate in a mock study section for a final review of the draft grant application.
  • NIH Mock Study Section. Investigators will have the opportunity to submit final drafts of their NIH grant applications for grantsmanship review by senior faculty and peer reviewers. These are designed to simulate an actual NIH study section.

PROGRAM RESOURCES

  • Professional grant writer consultations
  • Scientific networking
  • Foster and nurture multidisciplinary collaborations

OTHER CTSI RESOURCES

  • Watch videos of presentations from previous grant writing workshops
  • Request access to the UCLA CTSI Grant Library of funded NIH Grant applications

Contacts

If you have questions, please email CTSIWD@mednet.ucla.edu.

K Program Director

Mitchell Wong, MD, PhD at mitchellwong@mednet.ucla.edu

K Program Administrator

Lisa Chan at CTSIWD@mednet.ucla.edu