# The role of protease activated receptors on platelets

> **NIH NIH R01** · CASE WESTERN RESERVE UNIVERSITY · 2021 · $474,971

## Abstract

PROJECT SUMMARY/ABSTRACT
Venous thrombosis (VT) and its major complication, pulmonary embolism (PE), are often grouped together and
called venous thromboembolism (VTE). VTE is a major health problem that affect nearly 600,000 people each
year. The historical drivers of VTE are blood stasis, endothelial dysfunction, and hypercoagulation (Virchow’s
triad). It is now recognized that platelets and neutrophils have a critical initiating role. The molecular mechanisms
are only being uncovered. Given that hypercoagulation is a risk factor and thrombin activated protease activated
receptor 4 (PAR4) promotes procoagulant platelets, phosphatidyl serine (PS) exposure and subsequent
thrombin generation, we propose that PAR4 is an important contributor to VTE. The long-term goals of this
research program are to uncover the mechanisms of PAR4 activation at the molecular level and test these
mechanism in vivo to inform disease processes and potential drug development. The scientific premise of this
proposal is based our preliminary data showing that extracellular loop 3 (ECL3) of PAR4 coordinates with the
ligand binding site (LBS) during PAR4 activation. Further, mutations in either ECL3 or the LBS disrupt PAR4
signaling to the same degree. This points to an essential role for ECL3 in PAR4 activation. The overall objective
of this proposal is to 1) to determine how PAR4 contributes to the initiation and propagation of venous thrombosis
using mouse models, 2) conduct proof-of-concept studies using PAR4 antagonist to treat VT, 3) to translate our
recent structural insights on the PAR4 activation mechanism to PAR4 function in vivo. We will do this by taking
advantage a PAR4 variant in human platelets and a new mouse model. Our overall hypothesis is that the
sustained signaling from PAR4 on platelets is a driver of VTE and reduced PAR4 signaling from hypo-reactive
variants or pharmacological inhibitors will lead to protection from VTE. Our innovative approach will take
advantage of a new mouse model that recreates a polymorphism in ECL3 and will allow us to determine the
mechanism of how this polymorphism contributes to platelet function and thrombosis. The completion of the
proposed studies will accomplish two major advances. 1) we will be the first to specifically examine the role of
PAR4 in venous thrombosis. 2) we will continue to push our basic understanding of PAR activation mechanisms
by testing the observations from our structural studies in vivo to determine how these mechanisms operate in
physiological and pathophysiological contexts.

## Key facts

- **NIH application ID:** 10120909
- **Project number:** 2R01HL098217-10
- **Recipient organization:** CASE WESTERN RESERVE UNIVERSITY
- **Principal Investigator:** Marvin Thomas Nieman
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $474,971
- **Award type:** 2
- **Project period:** 2010-08-15 → 2025-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10120909

## Citation

> US National Institutes of Health, RePORTER application 10120909, The role of protease activated receptors on platelets (2R01HL098217-10). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10120909. Licensed CC0.

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