BLRD Research Career Scientist Award Application

This application is to support Dr. Lauren Ashley Cowart, PhD as a VA Research Career Scientist. Dr. Cowart has been VA funded since 2005 and has served as PI on 2 NIH R01 awards (currently funded through 2025), among other intra- and extramural support. Dr. Cowart began her independent career at the Ralph H. Johnson

VAMC and its academic affiliate, the Medical University of South Carolina (MUSC). While there she developed a robust research program with both NIH and VA support addressing the contribution of bioactive sphingolipids to obesity-related disease. These studies included seminal work on how different fatty acids (e.g unsaturated,

saturated, etc.) modified sphingolipid metabolism in cells, and how aberrant production of sphingolipids led to inflammation, maladaptive autophagy, oxidative stress, and other deleterious programs. These studies were conducted in a variety of organs and tissues including skeletal muscle, cardiac muscle, liver, and adipose tissue.

The research environment at Ralph H. Johnson VAMC was very rich, and while there she published over 40 manuscripts including 8 with prominent VA collaborators. From 2005-2017 Dr. Cowart advanced from a research track Assistant Professor to a tenured Associate Professor. In 2017, Dr. Cowart moved to the Hunter Holmes

McGuire VAMC whose academic affiliate is Virginia Commonwealth University. She immediately connected with Dr. Edward Lesnefsky, a VA cardiologist who serves co-investigator on her recent VA Merit award, and with whom she has active research projects and publications in preparation. Recently she has developed projects

with investigators at other VAMCs including Dr. Abhinav Diwan in St. Louis (John Cochran VAMC/Wash. U.), which has resulted in several grant applications and manuscripts in preparation, and Dr. Sushil Mahata in San Diego (VA San Diego Healthcare System/UCSD), with whom she has two manuscripts in development and has

been actively applying for both NIH and VA funding (through the collaborative Merit program). While the scale of the basic science research enterprise at Hunter Holmes McGuire is narrower than at Ralph H. Johnson, she continues to seek out and forge new collaborations within the local VA and national VA research community.

Dr. Cowart’s research addresses the constellation of metabolic diseases: type 2 diabetes, obesity, metabolic syndrome, and non-alcoholic fatty liver disease. In this context her work addresses molecular mechanisms by which sphingolipids regulate adipose tissue function, non-alcoholic fatty liver disease (NAFLD),

and myocardial dysfunction. Major published findings include that saturated vs. unsaturated fatty acids differentially regulate enzymes including sphingosine kinase 1 (SphK1) that produce the sphingolipid mediators sphingosine-1-phosphate (S1P) and ceramide, and that sphingosine-1-phosphate mediates NAFLD. These

findings led her to develop cell-specific knock outs of SphK1. Surprisingly, the adipocyte-specific SphK1 mouse demonstrated a basal diabetes-like phenotype, indicating a beneficial, homeostatic role for SphK1 in adipocytes. Furthermore, in liver, while depletion of SphK1 in hepatocytes partially attenuated inflammation in NAFLD,

female mice, and not males, developed an exacerbated fibrotic phenotype, which led to the discovery that estrogen-induced release of S1P from hepatocytes had an anti-fibrotic effect on hepatic stellate cells. While using mice on obesogenic diets for other studies, her group discovered that inhibition of sphingolipid biosynthesis

prevented mice from developing cardiac hypertrophy and features of diabetic cardiomyopathy. Further mechanistic studies in cells showed that specifically, Ceramide Synthase 5 mediated maladaptive autophagy, and in contrast Ceramide Synthase 2 mediated ROS production and mitophagy. These highly cited manuscripts

reflect the first work that has dissected the complexities of sphingolipid synthesis in heart disease to reveal distinct pathways that underlie pathology. These established studies have laid a foundation for current work further addressing bioactive sphingolipids in obesity-related pathology, alcoholic liver disease, and lipid

biomarker discovery. This award will provide stability and continuity as she continues to develop her research.