111C Holinstat, Michael - Thomas Jefferson University
Thomas Jefferson University
Sidney Kimmel Medical College
Department of Medicine

Holinstat, Michael

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Michael Holinstat, PhD

Contact Dr. Holinstat

1020 Locust Street
Suite 394
Philadelphia, PA 19107

(215) 955-6121
(215) 955-9170 fax

Research & 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.

Publications

Most Recent Peer-Reviewed Publications

  1. Common variants in the human platelet PAR4 thrombin receptor alter platelet function and differ by race
  2. Platelet 12-LOX is essential for FcγRIIa-mediated platelet activation
  3. Racial differences in resistance to P2Y12receptor antagonists in type 2 diabetic subjects
  4. MicroRNA expression differences in human hematopoietic cell lineages enable regulated transgene expression
  5. Human platelet microRNA-mRNA networks associated with age and gender revealed by integrated plateletomics
  6. Synthesis and structure-activity relationship studies of 4-((2-hydroxy-3-methoxybenzyl)amino)benzenesulfonamide derivatives as potent and selective inhibitors of 12-lipoxygenase
  7. Mechanism of race-dependent platelet activation through the protease-activated receptor-4 and Gq signaling axis
  8. The emerging role of oxylipins in thrombosis and diabetes
  9. Racial differences in human platelet PAR4 reactivity reflect expression of PCTP and miR-376c
  10. 12-lipoxygenase activity plays an important role in PAR4 and GPVI-mediated platelet reactivity
  11. MicroRNAs in platelet production and activation
  12. Dichotomous effects of exposure to bivalirudin in patients undergoing percutaneous coronary intervention on protease-activated receptor-mediated platelet activation
  13. Investigations of human platelet-type 12-lipoxygenase: Role of lipoxygenase products in platelet activation
  14. Protein kinase C regulation of 12-lipoxygenase-mediated human platelet activation
  15. Rap1-Rac1 circuits potentiate platelet activation
  16. We can do it together: PAR1/PAR2 heterodimer signaling in VSMCs
  17. Protein kinase Cα phosphorylates the TRPC1 channel and regulates store-operated Ca 2+ entry in endothelial cells (Journal of Biological Chemistry (2004) 279, (20941-20949))
  18. Discovery of potent and selective inhibitors of human platelet-type 12-lipoxygenase
  19. 12-lipoxygenase: A Potential Target for Novel Anti-Platelet Therapeutics
  20. Protease-activated receptor signaling in platelets activates cytosolic phospholipase a2α differently for cyclooxygenase-1 and 12-lipoxygenase catalysis
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