University of Virginia Health System

Dr. Kevin Lynch

Molecular Pharmacology of Lysophospholipid Mediators
The research efforts currently underway in my laboratory are focused on the molecular pharmacology of lysophospholipids. Lysophosphatidic acid and sphingosine-1-phosphate are structurally-related lipids that are prominent components of serum, and elicit a variety of responses (e.g., calcium mobilization, cytoskeletal rearrangements, growth, escape from apoptosis) from cultured cells. These effects are mediated by a set of at least eight G-protein-coupled receptors. We are interested particularly in developing a medicinal chemistry for the lysophospholipid mediators. For example, we have developed recently a series of 2-substituted N-acyl ethanolamide phosphate compounds that includes LPA receptor type selective agonists as well as LPA receptor antagonists. Such tools will provide insights into the roles of these mediators in physiologic and pathophysiologic settings.

Another area of investigation is the mechanism of action of the immune modulator, FTY720. This drug, after phosphorylation, is a potent sphingosine 1-phosphate mimetic that evokes a redistribution of lymphocytes from the circulating to secondary lymphoid compartments. We are now using our synthetic molecules to define what sphingosine 1-phosphate receptors mediate this phenotype as well as what kinases and phosphatases metabolize FTY720-like compounds. In exploring the structure-activity relationships of lysophospholipid mediators, we collaborate closely with Professor T.L. Macdonald's laboratory in the Department of Chemistry at UVA. Our research is supported by grants from the NIH and the pharmaceutical industry.