# Protease Activated Receptor and Thrombomodulin Signaling by Coagulation Proteases

> **NIH NIH R01** · OKLAHOMA MEDICAL RESEARCH FOUNDATION · 2020 · $437,000

## Abstract

Project Summary
Thrombomodulin (TM) is a type-1 integral membrane receptor which was identified and cloned as a
receptor for thrombin on endothelial cells. It is a multi-domain glycoprotein comprised of five distinct
domains that include an N-terminal lectin-like domain, followed by six epidermal growth factor
(EGF)-like domains, a membrane proximal Ser/Thr rich domain harboring chondroitin sulfate
glycosaminoglycans, a single spanning transmembrane domain and a cytoplasmic tail. TM switches
the specificity of thrombin from a procoagulant to an anticoagulant protease by binding to exosite-1
of thrombin via its EGF-like domains 4, 5, and 6 (TM456), thereby enabling thrombin to activate
protein C to activated protein C (APC). The exosite-1-dependent interaction of thrombin with TM on
endothelial cells can inhibit the thrombin recognition of protease-activated receptor 1 (PAR1) and
procoagulant substrates. TM also exerts antiinflammatory functions through its lectin-like domain by
unknown mechanisms. Recent results have indicated an association between loss of TM expression
and uncontrolled cell proliferation and metastasis. Based on our preliminary data in this application,
we hypothesize that thrombin can function as a true ligand for TM to elicit direct exosite-1-dependent
antiinflammatory signaling responses in vascular endothelial cells. We hypothesize that this function
of TM not only plays a cytoprotective role in response to inflammatory stimuli, but it may also
contribute to regulation of the vascular tone, maintenance and stabilization of the barrier
permeability function of the vasculature under steady-state conditions. We further hypothesize that
TM prevents thrombin from interacting with PAR1 on microvascular endothelial cells, thereby TM
directly transmitting the protective signaling function of thrombin via its cytoplasmic domain. We
have prepared a series of TM receptor constructs, recombinant APC and thrombin derivatives and
TM-null endothelial cells to investigate the following three Specific Aims: Aim 1 will investigate the
hypothesis that thrombin can function as a true ligand for TM to elicit direct cytoprotective signaling
responses in endothelial cells. Aim 2 will investigate the mechanism by which components of the
thrombin-TM-APC signaling axis inhibit the proinflammatory signaling function of high mobility group
box 1 (HMGB1) in endothelial cells. Aim 3 will develop a chlorhexidine gluconate (CG)-induced
peritoneal injury model and evaluate the mechanism of the cytoprotective function of the thrombin-
TM-protein C signaling axis in this model.

## Key facts

- **NIH application ID:** 9993552
- **Project number:** 5R01HL101917-10
- **Recipient organization:** OKLAHOMA MEDICAL RESEARCH FOUNDATION
- **Principal Investigator:** ALIREZA R. REZAIE
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $437,000
- **Award type:** 5
- **Project period:** 2010-04-01 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9993552

## Citation

> US National Institutes of Health, RePORTER application 9993552, Protease Activated Receptor and Thrombomodulin Signaling by Coagulation Proteases (5R01HL101917-10). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9993552. Licensed CC0.

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