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Principal Investigator: Lauren Ashley Cowart
Organization: VA VETERANS ADMINISTRATION HOSPITAL
Fiscal Year: 2024
Funding agency: Veterans Affairs
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.
Terms: <9-Octadecenoic Acid><Address><Adipocytes><Adipose Cell><Adipose tissue><Adult-Onset Diabetes Mellitus><Afghanistan><Alcoholic><Alcoholic Liver Diseases><Anabolism><Applications Grants><Atherosclerosis><Atherosclerotic Cardiovascular Disease><Attenuated><Autophagocytosis><Award><Back><Basic Research><Basic Science><Bibliography><Biological Markers><Blood><Blood Reticuloendothelial System><Body Tissues><Boozer><Brain Trauma><Cardiac><Cardiac Diseases><Cardiac Disorders><Cardiac Muscle Cells><Cardiac Myocytes><Cardiocyte><Cardiovascular Diseases><Career Development Awards><Career Development Awards and Programs><Career Development Programs K-Series><Cell Body><Cell Communication and Signaling><Cell Signaling><Cells><Ceramides><Collaborations><Communities><Complement Factor H><Dependent drinker><Development><Diabetes Mellitus><Diet><Disease><Disorder><Doctor of Philosophy><Dorsum><EXTMR><Environment><Enzyme Gene><Enzymes><Estrogens><Extramural><Extramural Activities><Factor H><Faculty><Fat Cells><Fatty Acids><Fatty Tissue><Female><Foundations><Funding><Grant><Grant Proposals><Health><Health Care Systems><Healthcare Systems><Heart Diseases><Heart Hypertrophy><Heart Muscle Cells><Heart failure><Heart myocyte><Heat Production><Hepatic Cells><Hepatic Disorder><Hepatic Parenchymal Cell><Hepatic Stellate Cell><Hepatocyte><Hexadecanoates><Hexadecanoic Acid><High Fat Diet><Inflammation><Intermediary Metabolism><International><Intracellular Communication and Signaling><Investigation><Investigators><Investments><Iraq><Ischemic Heart><Ischemic Heart Disease><Ischemic myocardium><Ito Cell><Joints><K-Awards><K-Series Research Career Programs><KO mice><Ketosis-Resistant Diabetes Mellitus><Knock-out><Knock-out Mice><Knockout><Knockout Mice><Laboratories><Laws><Link><Lipids><Lipocytes><Liver><Liver Cells><Liver diseases><Manuscripts><Mature Lipocyte><Mature fat cell><Maturity-Onset Diabetes Mellitus><Mediating><Mediator><Medical><Mental Depression><Mental disorders><Mental health disorders><Mentors><Metabolic Diseases><Metabolic Disorder><Metabolic Processes><Metabolic syndrome><Metabolism><Mice><Mice Mammals><Mitochondria><Molecular><Murine><Mus><Myocardial Ischemia><Myocardial depression><Myocardial dysfunction><Myocardium><Myristates><NAFLD><NIDDM><NIH><National Institutes of Health><Non-Insulin Dependent Diabetes><Non-Insulin-Dependent Diabetes Mellitus><Noninsulin Dependent Diabetes><Noninsulin Dependent Diabetes Mellitus><Null Mouse><Obese Mice><Obesity><Obesity associated disease><Obesity related disease><Oleic Acids><Organ><Over weight><Overweight><Oxidative Stress><PTSD><Palmitates><Palmitic Acids><Pathology><Pathway interactions><Patients with traumatic brain injury><Ph.D.><PhD><Phenotype><Population><Position><Positioning Attribute><Post-Traumatic Neuroses><Post-Traumatic Stress Disorders><Posttraumatic Neuroses><Predicting Risk><Preparation><Production><Psychiatric Disease><Psychiatric Disorder><Publications><Publishing><R-Series Research Projects><R01 Mechanism><R01 Program><Regulation><Research><Research Career Program><Research Grants><Research Personnel><Research Project Grants><Research Projects><Researchers><Risk Factors><Role><SPHK1 enzyme><Scientific Publication><Scientist><Seminal><Signal Transduction><Signal Transduction Systems><Signaling><Skeletal Muscle><Slow-Onset Diabetes Mellitus><South Carolina><Sphingolipids><Stable Diabetes Mellitus><T2 DM><T2D><T2DM><TBI Patients><Tetradecanoates><Therapeutic Estrogen><Thermogenesis><Thesaurismosis><Tissues><Training><Traumatic Brain Injury><Type 2 Diabetes Mellitus><Type 2 diabetes><Type II Diabetes Mellitus><Type II diabetes><United States National Institutes of Health><Universities><Unsaturated Fatty Acids><Veterans><Virginia><Voluntary Muscle><War><Work><adipose><adiposity><adult onset diabetes><alcohol induced hepatic injury><alcohol induced liver disorder><alcohol induced liver injury><alcohol related liver disease><alcohol use disorder><alcohol-associated liver disease><alcohol-induced hepatic dysfunction><alcohol-induced liver disease><alcohol-induced liver dysfunction><alcohol-mediated liver dysfunction><alcohol-mediated liver injury><alcohol-related liver disease><alcoholic liver injury><associate faculty><associate professor><atheromatosis><atherosclerotic disease><atherosclerotic vascular disease><attenuate><attenuates><autophagy><base><bases><bio-markers><biologic marker><biological signal transduction><biomarker><biomarker discovery><biosynthesis><cardiac dysfunction><cardiac failure><cardiac hypertrophy><cardiac ischemia><cardiac muscle><cardiomyocyte><cardiovascular disorder><career><ceramide synthase><cis-9-Octadecenoic Acid><coronary ischemia><corpulence><depression><developmental><diabetes><diabetic cardiomyopathy><diabetic cardiopathy><diabetic cardiopathy disease><diabetic cardiopathy disorder><diabetic cardiovascular disease><diabetic cardiovascular disorder><diets><dihydroceramide desaturase><ethanol induced hepatic injury><ethanol induced liver disorder><ethanol induced liver injury><ethanol liver disease><ethanol use disorder><ethanol-induced hepatic dysfunction><ethanol-induced liver disease><ethanol-induced liver dysfunction><ethanol-mediated liver dysfunction><ethanol-mediated liver injury><experience><fat metabolism><fatty liver disease><forecasting risk><forging><heart disorder><heart dysfunction><heart ischemia><heart muscle><hepatic body system><hepatic disease><hepatic organ system><hepatopathy><high risk><inhibitor><interest><ketosis resistant diabetes><lipid metabolism><liver disorder><maturity onset diabetes><member><mental illness><metabolism disorder><mid-career faculty><midcareer faculty><mitochondrial><mouse model><murine model><myocardial ischemia/hypoxia><myocardium ischemia><non-alcohol fatty liver disease><non-alcoholic><non-alcoholic fatty liver disease><non-alcoholic liver disease><nonalcoholic><nonalcoholic fatty liver disease><novel><ob/ob mouse><obesigenic><obesogenic><pathway><post-trauma stress disorder><posttrauma stress disorder><predict risk><predict risks><predicted risk><predicted risks><predicting risks><predictive risk><predicts risk><preparations><prevent><preventing><problem drinker><professor><programs><psychiatric illness><psychological disorder><risk prediction><risk predictions><social role><sphingosine 1-phosphate><sphingosine kinase-1><synergism><traumatic brain damage><traumatic brain injury patients><traumatic neurosis><type 2 DM><type II DM><type two diabetes><white adipose tissue><yellow adipose tissue>