# Vascular Thiol Isomerases in Thrombosis

> **NIH NIH R01** · BETH ISRAEL DEACONESS MEDICAL CENTER · 2020 · $817,641

## Abstract

Project Summary/Abstract
Thiol isomerases serve a critical role in thrombus formation, as demonstrated in several independent
models of thrombus formation using genetic deletion of thiol isomerases, inhibitory antibodies, and small
molecule antagonists. A therapy targeting protein disulfide isomerase (PDI) is currently in phase II/III
studies to evaluate its efficacy and safety as an antithrombotic. Yet despite compelling evidence that thiol
isomerases function in thrombus formation, little is known about how these enzymes contribute to
thrombosis. Vascular thiol isomerases - PDI, ERp5, and ERp57 - control the formation and cleavage of
allosteric disulfide bonds and modify protein function. The nature of the modifications and how they impact
protein function are largely unstudied. Using molecular, cellular and whole animal studies of thrombus
formation, we will address critical questions related to the role of thiol isomerases in thrombus formation. In
Aim 1, we will determine how thiol isomerases escape retention in the endoplasmic reticulum, how thiol
isomerases are organized and packaged into granules in platelets and endothelial cells, and the
mechanisms that regulate the exocytosis of thiol isomerases in these cells. In Aim 2, we will identify the
pathways and mechanisms that link vascular thiol isomerases to platelet thrombus formation and fibrin
generation. Protein components of this initiation pathway will be identified using mechanism-based kinetic
trapping to identify substrates from platelets, plasma, and endothelial cells. In Aim 3, we will evaluate the
regulation of thiol isomerases by nitric oxide and test the ability of thiol isomerases to control nitric oxide
during thrombus formation. We will study how platelet receptors are activated by thiol isomerase-mediated
denitrosylation. We will also image nitric oxide and reactive oxygen species in live mice to assess the
control of nitric oxide and oxidative stress by thiol isomerases. This project will provide new fundamental
knowledge of how thiol isomerases are released following vascular injury, how they modify vascular protein
substrates, and how they are regulated. Given the paucity of knowledge of extracellular thiol isomerase-
mediated pathways, these studies will provide essential information for beginning to decrypt this essential,
yet largely unexplored, layer of thrombus formation.

## Key facts

- **NIH application ID:** 9912828
- **Project number:** 5R01HL136394-04
- **Recipient organization:** BETH ISRAEL DEACONESS MEDICAL CENTER
- **Principal Investigator:** JOSEPH E ITALIANO
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $817,641
- **Award type:** 5
- **Project period:** 2017-04-01 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9912828

## Citation

> US National Institutes of Health, RePORTER application 9912828, Vascular Thiol Isomerases in Thrombosis (5R01HL136394-04). Retrieved via AI Analytics 2026-06-02 from https://api.ai-analytics.org/grant/nih/9912828. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*