Dr. Schwartzman Awarded $2.2 Million NIH Grant
Michal Laniado Schwartzman, Ph.D.'s Project Explores the Underlying Mechanisms of Obesity-driven Cardiovascular and Metabolic Diseases
Michal Laniado Schwartzman, Ph.D., professor and chair of Pharmacology, professor of medicine and associate professor of ophthalmology, has been awarded a $2,268,684 four-year grant from the National Heart, Lung, and Blood Institute. The overall goal of this proposal is aimed at identifying cellular mechanisms that link activation of the G-protein coupled receptor 75 (GPR75) to obesity-driven metabolic and cardiovascular complications.
“Obesity is now considered a worldwide epidemic and a risk factor for insulin resistance, diabetes, cardiovascular diseases, liver disease and immunological/infectious diseases such as COVID-19. Our recent findings in humans and mice identified the G-protein-coupled receptor 75 (GPR75) and its ligand, the lipid mediator 20-hydroxyeicosatetraenoic acid (20-HETE), as significant contributors to obesity and its associated cardiovascular and metabolic complications. Understanding the mechanisms by which activation of GPR75 leads to exacerbation of diet-driven adiposity, insulin resistance and vascular dysfunction will lead to novel therapeutics to treat obesity and its associated complications.”
In the last few years, Dr. Schwartzman’s lab in collaboration with Victor Garcia, Ph.D. ‘15, assistant professor of pharmacology, provided strong evidence that GPR75 is the receptor to which 20-HETE, a vasoactive and pro-inflammatory lipid mediator, binds and through which it triggers its actions. 20-HETE has been implicated in the development and progression of cardiovascular and metabolic diseases including hypertension, stroke, myocardial infarction, diabetes and obesity/metabolic syndrome.
The funded project centers on the relationship between obesity and the risk of cardiovascular complications via the lens of 20-HETE-GPR75 pairing in two specific tissues critical to the pathogenesis of metabolic and cardiovascular diseases, the adipose tissue and the vascular endothelium. This project is based on decades of research studying the biology of 20-HETE, determining its sources and bioactions, and identifying its cellular targets including its high affinity receptor, GPR75. This decade-long work culminated with a publication in Science (2021) by a large scientific consortium including Regeneron, Schwartzman’s and Garcia’s labs, and others, uncovering several loss of function GPR75 variants associated with leanness and protection from obesity. This finding matches results from GPR75 null mice which are protected from high-fat diet-driven adiposity and insulin resistance. Using transgenic mice, medicinal chemistry and state-of-the art methodology and equipment, the project seeks to understand how GPR75 deficiency protects against obesity and its complications.