Project 4. Platelet accumulation is both a hallmark of hemostasis and a contributor to heart attacks and strokes. Previous studies have focused on identifying individual signaling molecules that support platelet activation. Here we attempt a paradigm shift, first, by approaching platelet activation and the hemostatic response as the product of the global platelet signaling network rather than any one pathway, and, second, by linking testable ideas about the function of that network to real time observations of platelet activation in vivo and in vitro. We and others have shown that hemostatic thrombi have a characteristic structure in which a core of fully-activated platelets is overlaid with an unstable shell of less-activated platelets. We have recently extended this model by showing that the core and shell are regulated by different elements of the platelet signaling network and demonstrating that increased packing density in the core affects thrombin distribution, contact-dependent signaling and the influx of plasma-borne molecules. The proposed studies will build upon this background, merging mechanism-driven and observational approaches to determine how thrombus structure evolves define its relationship the platelet signaling network.
In Aim #1 we will use intravital confocal and multi-photon microscopy to compare platelet activation in the micro- and macro-vasculature. Dyslipidemia will be used to study the impact of acquired disorders of platelet reactivity.
In Aim #2 we will use human platelets, transgenic mouse lines and pharmacologic agents to examine the relationships between the platelet signaling network and thrombus structure.
In Aim #3 we will focus on contact-dependent signaling events between platelets, testing the novel hypothesis that these events are segregated spatially and temporally into pathways that either promote or restrain the thrombus core. Through these aims, we hope to define the mechanisms that drive thrombus formation, account for differences in the clinical impact and bleeding risk associated with different antiplatelet agents, and show how pathological conditions can subvert normal responses by their impact on the platelet signaling network

Public Health Relevance

Platelet activation is part of the normal response to vascular injury, producing a plug that limits blood loss. Thrombosis occurs when platelets are activated inappropriately, blocking blood flow and damaging tissues such as the heart and brain. The goal of this project is to better understand the molecular basis of platelet activation and translate that understanding into improved methods to prevent thrombosis..

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
2P01HL040387-26A1
Application #
8694341
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Project Start
Project End
Budget Start
2014-05-16
Budget End
2015-04-30
Support Year
26
Fiscal Year
2014
Total Cost
$458,582
Indirect Cost
$171,968
Name
University of Pennsylvania
Department
Type
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
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