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

> **NIH NIH R35** · UNIVERSITY OF ILLINOIS AT CHICAGO · 2023 · $80,190

## Abstract

Abstract of Parent Grant:
 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, but
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 𝛽2 integrins, 𝛼L𝛽2 and 𝛼m𝛽2, 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 G𝛼13 to an ExE
motif conserved in the cytoplasmic domains of both 𝛽2 and 𝛽3. Project 1 of this proposal
is to investigate the mechanisms of G𝛼13-dependent integrin outside-in signaling.
Project 2 is to investigate the important role of 𝛽3 outside-in signaling in shear- and
agonist-induced platelet procoagulant activity, and the conceptual basis for targeting
G𝛼13- 𝛽3 interaction to develop a dual anti-platelet/anti-coagulant drug with minimal
bleeding risk. Project 3 is to investigate the role of G𝛼13-dependent 𝛽2 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:** 10772297
- **Project number:** 3R35HL150797-04S1
- **Recipient organization:** UNIVERSITY OF ILLINOIS AT CHICAGO
- **Principal Investigator:** Xiaoping Du
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $80,190
- **Award type:** 3
- **Project period:** 2020-06-01 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10772297

## Citation

> US National Institutes of Health, RePORTER application 10772297, Mechanisms of integrin signaling and a new anti-platelet/anti-inflammatory approach (3R35HL150797-04S1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10772297. Licensed CC0.

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