# Targeting Platelet Endocytosis and Exocytosis to Control Thrombosis

> **NIH VA I01** · VA MEDICAL CENTER - LEXINGTON, KY · 2021 · —

## Abstract

World-wide, spurious thrombosis accounts for 1 of 4 non-communicable disease deaths.
Cardiovascular disease is a leading killer of aging US veterans and is the major cause of death in older
female veterans. Understanding how to modulate thrombosis will significantly aide the VA's mission to
improve veterans' health. Normally platelets respond to vascular damage and secrete granule cargo
that are essential for recruiting more platelets and for generating a thrombus. This releasate promotes
normal sequelae but can also contribute to occlusive pathologies such as strokes and heart attacks. In
platelets, VAMPs, SNAP-23, and Syntaxin-11 form a membrane-spanning complex that mediates
exocytosis. Formation of this complex requires a host of SNARE-regulators, e.g., Munc18b,
STXBP5/tomosyn-1, and granuphilin/SLP4; however, the mechanisms by which these proteins control
the complexity of the platelet release reaction (its rate, extent, and content) is uncertain. Platelets are
also capable of other cellular processes (i.e., RNA splicing, translation, glycosylation, autophagy);
however, their effects on platelet function are still unknown. Our data suggest that endocytosis affects
thrombus growth by modulating platelet spreading and platelet-platelet contacts. Our goal is to
manipulate the membrane trafficking in platelets, both endocytosis and exocytosis, in order to
modulate occlusive thrombosis with only modest effects on hemostasis. To reach this goal, we
must probe the molecular mechanisms of exocytosis. Our specific focus will be on Syntaxin-11
regulators. We will also use an endocytosis defective mouse strain to define the roles of endocytosis in
thrombosis and hemostasis. Two aims are proposed: 1) Define the network of protein-protein
interactions that affect Syntaxin-11-mediated membrane fusion and granule cargo release; and
2) Determine the roles of platelet endocytosis in hemostasis. To complete these aims, we will
employ biochemical assays to define the interactions between the SNARE regulators and in vitro and
in vivo functional assays, using transgenic mice, to define the roles of the specific Syntaxin-11
regulators and of endocytosis in thrombosis and hemostasis. Our results will expand the understanding
of the molecular requirements and the sequence of protein-protein interactions controlling platelet
exocytosis. We will also expand the mechanistic understanding of what cellular processes platelets can
perform (i.e., endocytosis) and why they are important. Our results will be significant to the field since
they will provide the needed mechanistic insights to identify potential targets for therapeutic intervention
and to evaluate the relevance of the increasing volume of gene/risk associations that are guiding patient
treatment strategies. This will enhance the anti-thrombotic treatment options available for the care of
aging veterans.

## Key facts

- **NIH application ID:** 10046272
- **Project number:** 5I01BX003877-04
- **Recipient organization:** VA MEDICAL CENTER - LEXINGTON, KY
- **Principal Investigator:** SIDNEY Waldo WHITEHEART
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2021
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2017-10-01 → 2022-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10046272

## Citation

> US National Institutes of Health, RePORTER application 10046272, Targeting Platelet Endocytosis and Exocytosis to Control Thrombosis (5I01BX003877-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10046272. Licensed CC0.

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