Michael Holinstat, PhD
Philadelphia, PA 19107
(215) 955-9170 fax
Most Recent Peer-reviewed Publications
- Synthesis and structure-activity relationship studies of 4-((2-hydroxy-3-methoxybenzyl)amino)benzenesulfonamide derivatives as potent and selective inhibitors of 12-lipoxygenase
- Racial differences in human platelet PAR4 reactivity reflect expression of PCTP and miR-376c
- The emerging role of oxylipins in thrombosis and diabetes
- 12-lipoxygenase activity plays an important role in PAR4 and GPVI-mediated platelet reactivity
- MicroRNAs in platelet production and activation
Research and Clinical Interests
My lab focuses on understanding the complex signaling mechanisms by which undergo in order to regulate hemostasis and thrombosis. The work in my lab focuses on three primary areas of platelet research spanning from a basic science and drug discovery program to clinical and translational projects including a clinical trial focused on platelet function in type 2 diabetes mellitus. This work is fully funded by three National Institutes of Health grants (NIH R01 grants), support from the American Heart Association (AHA), the Parenteral Drug Association Foundation (PDAF), and the Cardeza Foundation for Hematologic Research at Thomas Jefferson University.
One project in my lab focuses on identifying the inherent racial differences in platelet function between blacks and whites. This clinical project investigates some of the underlying genetic differences in blacks and whites which predispose some people to a higher risk for thrombosis and stroke while sparing others. Through this effort we will be able to determine for the first time how to differentially treat patients based on their genetic/racial background. This area of research, often termed “individualized medicine” has the potential to shift our mode of treatment from disease to patient by understanding that not all treatments will equally benefit every patient who presents with a thrombotic event and more importantly prevention of thrombotic events may differ based on genetic or racial background. Early findings in this study have already shown that blacks express a higher level of the thrombin receptor PAR4 and have uncovered a novel protein in the human platelet (absent in the mouse platelet), phosphatidylcholine transfer protein (PCTP), which appears to play an important role in platelet activation and is highly expressed in platelets from blacks compared to whites.
A second area of focus in the lab is identifying how platelet activation is regulated by the enzyme 12-lipoxygenase (12-LOX). Similar to COX-1, 12-LOX oxidizes free fatty acids in order to form bioactive metabolites (called eicosanoids). Our lab has recently shown that the 12-LOX eicosanoids derived from arachidonic acid in the platelet are pro-thrombotic and we, along with our collaborators across the country, have developed the first selective inhibitor against human 12-LOX activity. This new class of inhibitors prevents agonist-mediated platelet activation and clot formation in human platelets. Subsequently, we also identified that 12-LOX oxidizes 0mega-6 fatty acids to produce a novel eicosanoid, 12-HETrE, which is a potent inhibitor of platelet function. We are currently trying to identify the underlying mechanisms by which 12-HETrE protects against platelet activation, clot formation, and stroke.
A third focus of the lab takes advantage of our basic scientific observations that altering the fatty acid content on the platelet may allow for formation of 12-LOX metabolites which would protect type 2 diabetics from suffering a thrombotic event. This translational project investigates in animal and patients the potential for omega-3 and omega-6 fatty acids and their 12-LOX eicosanoids to prevent platelet activation and unwanted thrombosis. This is an important area in diabetes research as 65% of deaths in type 2 diabetes mellitus are due to thrombosis and stroke.