The UCLA CTSI R Bridge Award is for highly qualified, new investigators who conduct interdisciplinary and translational research. These awards are specifically intended to help new investigators make the critical transition to independent NIH R01 funding, allowing those who have received competitive scores on their first R01 proposals to the National Institutes of Health (NIH) to remain scientifically productive and strengthen their proposals for resubmission.
Project title: Molecular mechanisms of hypervirulence in antibiotic-resistant Pseudomonas aeruginosa
Antibiotic development has stalled during a time when antibiotic resistant bacteria are becoming increasingly more prevalent and dangerous to human health. We recently found that some antibiotic resistant bacteria also become deadlier as a result of their antibiotic resistance, even when antibiotics are not being used to treat the infection. The goals of this research are to determine why antibiotic resistant bacteria are deadlier than antibiotic susceptible bacteria and to leverage this information for the development of new therapies to treat antibiotic resistant bacteria.
Project title: Tissue-engineered models of glioblastoma tumor invasion and recurrence
Glioblastoma (GBM) is a uniformly fatal brain cancer with poor response to treatment and high rates of recurrence. This proposal describes application of a tissue-engineered model of the interface between GBM and its associated microvessels for systematic characterization of the mechanisms by which peritumoral vasculature promote GBM cells to migrate away from primary tumors, eventually leading to tumor recurrence. We will investigate 1) the role of specific cues in the tumor microenvironment on the migratory phenotype of GBM cells using tissue-engineered platform for 3D culture and 2) how these cues differentially affect distinct subpopulations of cells within heterogeneous tumors using single-cell RNA sequencing. Aim 1 will investigate effects of mechanical cues and Aim 2 effects of biochemical cues present in the microvessel niche on migratory function and phenotype of GBM cells.
Project title: Targeting the regulatory mechanism of hyphae to lateral yeast growth as a novel therapeutic approach against candidiasis
A single species Candida albicans, causes half of all invasive fungal infections in humans. C. albicans hyphae produce yeast cells from their lateral septal regions, coined as “lateral yeasts”. These lateral yeasts are always found with hyphae at the site of active infection, are the major cells that re- enter the bloodstream and establish distal foci of infection. We identified the first regulator of hyphae-to-lateral yeast growth, PES1, and have shown that depleting PES1 in vivo can abrogate disseminated candidiasis as well as biofilm-associated candidemia. Here, using protein biochemistry assays, we propose to delineate how signaling through Ras-PKA regulates Pes1. We will identify other cognate regulators that interact with Pes1 to control lateral yeast growth, and use this information to discover novel compounds that can interrupt hyphae to lateral yeast growth and disseminated candidiasis. Ultimately, better outcomes for patients with indwelling medical devices is the goal of this application.
Project title: Hormonal Mechanisms of Sleep Restriction
Insufficient sleep is common, and leads to insulin resistance, a major factor in the development of type 2 diabetes mellitus. This proposal attempts to reveal the hormonal mechanisms underlying the link between insufficient sleep with insulin resistance. The studies have the potential to outline specific interventions to modify the deleterious hormonal changes, and significantly impact the rising incidence of diabetes mellitus.
Project title: Understanding Retention in Malawi's Option B+ Program
Option B+ emphasizes rapid initiation of antiretroviral therapy (ART) in all pregnant and breastfeeding women and continuation for life, with the goal of reducing mother-to-child transmission (MTCT) and improving health of women. According to the Malawi Ministry of Health, 23% of women started on ART as part of Option B+ are lost from the program by 12 months. Despite this data, there have been no large studies characterizing challenges that women have staying in care and reasons why they may stop taking medications. Taking advantage of UCLA’s long-term relationship with a PEPFAR/USAID collaborator in Malawi, we will perform a mixed-methods study that will begin with interviews with women who have been lost to follow-up from Option B+ (Aim1) to inform a survey that will be used to examine characteristics that distinguish women who stay in care from those who are lost from care (Aim 2).
Project title: Pathobiology and Mechanism of Progesterone Resistance in Human Endometrial Cancer
Endometrial cancer is the most common gynecologic cancer in the U.S. It originates from the endometrium, a hormonally sensitive cell layer inside of the uterus. While endometrial cancer is often curable in early stages, current therapies (surgery, radiation and chemotherapy) are often ineffective in patients with advanced disease and they can have debilitating side effects. Endometrial cancers can respond to hormonal treatment, but unlike current therapies for other hormone responsive cancers (like breast and prostate) hormonal treatment is not commonly used in endometrial cancer patients. One reason is lack of research in the field. We aim to change this by developing biomakers that can predict if a patient’s endometrial cancer can be successfully treated with a hormone called progesterone. Simultaneously, we are exploring ways to make progesterone resistant tumors respond to hormonal therapy. Our overall goal is to improve lives of thousands of women affected by this gynecologic malignancy.