# Determining the Platelet Signaling Pathway(s) Critical in Venous Thrombosis Pathogenesis" it might change in the process of editing

> **NIH NIH F31** · UNIV OF NORTH CAROLINA CHAPEL HILL · 2022 · $29,432

## Abstract

Project summary
Venous thrombosis (VT) affects close to a million Americans annually. One of the main triggers
of VT is flow restriction, which leads to vascular inflammation and initiation of thrombus
formation. Venous thrombi contain platelets and changes in platelet count correlate with VT
outcome in humans and mice. However, little is known about the molecular mechanisms by
which these cells contribute to venous thrombogenesis. The goal of my project is to
systematically investigate on how major platelet signaling pathways facilitate platelet/leukocyte
adhesion, thrombus growth, and thrombus consolidation following vascular stenosis in mice. My
main hypothesis is that the platelet signaling pathways required during venous thrombogenesis
are similar to those required for securing vascular integrity at sites of inflammation. Specifically,
my study aims to delineate if and how platelet G-protein-coupled receptors (GPCRs),
immunoreceptor tyrosine-based activation motif (ITAM) receptors, and the Rap1-talin1-integrin
signaling axis contribute to VT development in mice. Consistent with my main hypothesis, I
expect ITAM signaling and talin1 to be more important for venous thrombogenesis than GPCRs
and Rap1. The following transgenic mouse lines with documented defects in platelet integrin
signaling will be used: CLEC2 (Clec2fl/flpf4-Cre+), Rap1 (Rap1afl/flRap1bfl/flpf4-Cre+) and
Talin1 (Tln1fl/flpf4-Cre+). Pharmacological inhibition of the collagen receptor, GPVI, the ITAM
signaling molecule, Bruton’s tyrosine kinase (Btk), and 1 and 3 integrins will also be used. In
vivo, VT will be induced by partially ligating the inferior vena cava (IVC stenosis), the gold
standard model for VT studies in mice. Mice will be sacrificed after 48 hrs of flow restriction and
thrombi harvested and weighed. To investigate the role of platelets in the initiation of VT, I will
use intravital imaging of the IVC 2 to 3 hours after ligation and quantify platelet and leukocyte
adhesion to the IVC wall. Whole blood clot contraction and susceptibility to lysis studies will
provide important information on the role of specific platelet signaling pathways during thrombus
consolidation and resolution. Successful completion of the proposed studies will elucidate
platelet signaling pathways that contribute to the initiation, propagation, and stability of venous
thrombi. This information may lead to the identification of new platelet-based therapeutic targets
for the prevention/treatment of VT.

## Key facts

- **NIH application ID:** 10540297
- **Project number:** 5F31HL154562-02
- **Recipient organization:** UNIV OF NORTH CAROLINA CHAPEL HILL
- **Principal Investigator:** Jean Marie Niyitegeka Mwiza
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $29,432
- **Award type:** 5
- **Project period:** 2021-02-01 → 2022-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10540297

## Citation

> US National Institutes of Health, RePORTER application 10540297, Determining the Platelet Signaling Pathway(s) Critical in Venous Thrombosis Pathogenesis" it might change in the process of editing (5F31HL154562-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10540297. Licensed CC0.

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