# Mechanisms of integrin signaling and a new anti-platelet/anti-inflammatory approach

> **NIH NIH R35** · UNIVERSITY OF ILLINOIS AT CHICAGO · 2020 · $959,400

## Abstract

Thrombotic cardiovascular diseases remain the leading cause of death in US and world. Blood platelets play
key roles in both hemostasis and thrombosis. Not only do platelets adhere and aggregate to form thrombi at
the site of vascular injury, platelets also facilitate coagulation (formation of a fibrin clot). Both platelet thrombus
formation and coagulation are important contributors to the morbidity and mortality of thrombotic diseases such
as heart attack and stroke. Thus, anti-platelet drugs and anti-coagulants were developed and are clinically
used to prevent and treat thrombosis. However, current anti-platelet drugs and anti-coagulants have
deficiencies. First, anti-platelet drugs and anti-coagulants all have the major adverse effect of bleeding, which
can be life-threatening. Furthermore, anti-platelet drugs are not as effective in treating coagulation, and vice
versa, but combined use of anti-platelets and anti-coagulants greatly exacerbates bleeding risk. Thus, it would
be highly significant to develop dual anti-platelet and anti-coagulant drugs, which do not cause bleeding.
Furthermore, thrombosis can be induced by chronic and acute inflammatory conditions such as atherosclerosis
and sepsis. Conversely, thrombosis induces and exacerbates inflammation. Thus, it is also highly desirable to
develop a drug that is more potent than aspirin in anti-thrombotic and anti-inflammatory efficacy. The Integrin
family of adhesion receptors plays key roles in both in platelets and leukocytes. Platelet integrin aIIbb3 (GPIIb-
IIIa), upon activation by inside-out signaling stimulated by agonists, not only mediates platelet adhesion and
thrombus formation, but also transmits outside-in signals leading to thrombus expansion and occlusive
thrombosis, but is dispensable for primary hemostasis. Leukocyte b2 integrins, aLb2 and amb2, mediate
leukocyte adhesion and outside-in signaling, leading to cell migration, cytokine release, phagocytosis, etc., and
thus play critical roles in inflammation. We recently showed that outside-in signaling of integrins requires the
binding of G protein subunit Ga13 to an ExE motif conserved in the cytoplasmic domains of both b2 and b3.
Project 1 of this proposal is to investigate the mechanisms of Ga13-dependent integrin outside-in signaling.
Project 2 is to investigate the important role of b3 outside-in signaling in shear- and agonist-induced platelet
procoagulant activity, and the conceptual basis for targeting Ga13-b3 interaction to develop a dual anti-
platelet/anti-coagulant drug with minimal bleeding risk. Project 3 is to investigate the role of Ga13-dependent b2
integrin outside-in signaling in proinflammatory functions of leukocytes and in severe sepsis, and the
conceptual basis for developing dual anti-thrombotic and anti-inflammatory drugs for treating severe sepsis
and other thrombo-inflammatory conditions.

## Key facts

- **NIH application ID:** 9894367
- **Project number:** 1R35HL150797-01
- **Recipient organization:** UNIVERSITY OF ILLINOIS AT CHICAGO
- **Principal Investigator:** Xiaoping Du
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $959,400
- **Award type:** 1
- **Project period:** 2020-06-01 → 2027-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9894367

## Citation

> US National Institutes of Health, RePORTER application 9894367, Mechanisms of integrin signaling and a new anti-platelet/anti-inflammatory approach (1R35HL150797-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9894367. Licensed CC0.

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