# Platelet ERO1alpha in thrombosis and hemostasis

> **NIH NIH F30** · UNIVERSITY OF ILLINOIS AT CHICAGO · 2021 · $15,018

## Abstract

PROJECT SUMMARY/ABSTRACT
It was reported that in 2009 alone, 32% of all deaths in the US resulted from cardiovascular disease, including
acute coronary syndrome, stroke/transient ischemic attack, and peripheral artery disease. Underlying these
pathologies is increased platelet activity. Platelets play an essential role in hemostasis and thrombosis. Following
vascular and tissue damage, platelets rapidly adhere to the site of injury and secrete granular contents that
recruit and activate additional platelets, culminating in the formation of thrombi through the interaction between
integrin αIIbβ3 and fibrinogen. Because of the essential role of integrin αIIbβ3 in platelet thrombus formation,
antagonists of the integrin have been developed. However, direct inhibition of ligand binding to integrin αIIbβ3
could impair hemostasis and increase the risk of bleeding. Thus, many efforts have been put forward to develop
inhibitors blocking integrin αIIbβ3 function or signaling.
Numerous studies have now characterized the role of thiol-disulfide bond exchange as a regulatory mechanism
for integrin αIIbβ3. Using real-time intravital microscopy, we and others demonstrated that the isomerase activity
of cell surface protein disulfide isomerase (PDI), a prototypical thiol isomerase, plays a critical role in regulating
integrin β3 activation and thrombus formation at the site of vascular injury, thereby suggesting PDI to be a novel
therapeutic target for the treatment of thrombosis. However, blocking extracellular PDI compromised hemostatic
function in mice as assessed by tail bleeding times. These results warrant the need for further research into how
extracellular PDI activity is regulated following vascular injury.
In the endoplasmic reticulum (ER), PDI catalyzes thiol-disulfide oxidation, reduction, and isomerization during
protein folding and ER oxidoreductin 1α (ERO1α) is the key protein responsible for accepting the electrons from
reduced PDI to oxidize PDI, regenerating its activity. In this comprehensive proposal, we will test the hypothesis
that platelet surface ERO1α modulates the ligand-binding function of integrin αIIbβ3 by controlling PDI activity and
facilitates platelet aggregation during thrombosis. The proposed studies will provide mechanistic insight into an
innovative approach to downregulate the ligand-binding function of integrin αIIbβ3 by inhibition of the ERO1α-PDI
signaling axis and may lead to the development of novel therapeutic strategies.

## Key facts

- **NIH application ID:** 10093117
- **Project number:** 5F30HL134296-05
- **Recipient organization:** UNIVERSITY OF ILLINOIS AT CHICAGO
- **Principal Investigator:** Alan Tseng
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $15,018
- **Award type:** 5
- **Project period:** 2017-01-01 → 2021-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10093117

## Citation

> US National Institutes of Health, RePORTER application 10093117, Platelet ERO1alpha in thrombosis and hemostasis (5F30HL134296-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10093117. Licensed CC0.

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