# Mechanotransduction of platelet receptors GPIb and GPIIb-IIIa

> **NIH NIH R01** · GEORGIA INSTITUTE OF TECHNOLOGY · 2023 · $494,755

## Abstract

Project Summary/Abstract
Platelets are arguably the most important cellular participant in hemostasis and thrombosis. Many therapeutic
strategies target platelet molecules to inhibit their functions in thrombosis. In particular, two membrane adhesion
receptors, glycoprotein (GP) Ib-IX and GPIIb-IIIa (integrin IIb3), cooperatively mediate platelet adhesion and
thrombus formation under high shear flow, and thus are ideal targets for inhibiting thrombosis in stenotic arteries
as well as in microvasculature. Also, all anti-platelet drugs currently being used to treat thrombosis clinically have
adverse hemorrhagic side effects, because the platelet plug formation required to stop bleeding is also inhibited.
Under the support of this grant in its past period, we and others showed that both GPIbα and IIb3 are
mechanoreceptors capable of receiving mechanical cues. We found that GPIb mechano-signaling leads to
integrin inside-out signaling, which activates IIb3 from the inactive state having a bent conformation and a
closed headpiece (BC) with a low affinity and short bond lifetime for ligand to an intermediate state having an
extended conformation but a closed headpiece (EC) with an intermediate affinity and intermediate bond lifetime
for ligand, which is distinct from the fully active state of IIb3 often seen in platelets stimulated by soluble agonists
that has an extended conformation and an open headpiece (EO) with a high affinity and long bond lifetime for
ligand. Significantly, the intermediate state of IIb3 mediates the formation of “biomechanical thrombi”, consisting
of transient and unstable platelet aggregates resembling the dynamic outer layer of an in vivo thrombus formed
under high shear blood flow, which is distinct from platelet aggregates underneath the outer layer that are further
stimulated by released soluble agonists and where IIb3 are further activated to the fully active EO state. Further
activation from the intermediate state to the fully active state can also be induced by IIb3 outside-in mechano-
signaling, which also induces further activation of platelets. These data highlight the role of force-induced
signaling – mechano-signaling – of, by, and between GPIb-IX and IIb3, and their unique importance in thrombus
formation. Our overarching hypothesis is that a balanced regulation of mechano-signals of GPIbα and IIb3, and
their synergy with biochemical signals induced by soluble platelet agonists, holds the promise to control
thrombosis without unsetting hemostasis. The specific aims are to elucidate 1) the roles of 14-3-3ζ and filamin
A on GPIbα ligand-binding, unfolding and mechano-signaling, 2) the mechanism of GPIb-IX mechanosensing-
induced intracellular signaling pathway leading to integrin activation, and 3) the roles of G13, talin1 and Rap1
on GPIIb-IIIa binding, conformation and mechano-signaling. These studies will characterize the ligand-binding
and signaling of of two major platelet mechanoreceptors, G...

## Key facts

- **NIH application ID:** 10670136
- **Project number:** 5R01HL132019-07
- **Recipient organization:** GEORGIA INSTITUTE OF TECHNOLOGY
- **Principal Investigator:** Cheng Zhu
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $494,755
- **Award type:** 5
- **Project period:** 2016-04-01 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10670136

## Citation

> US National Institutes of Health, RePORTER application 10670136, Mechanotransduction of platelet receptors GPIb and GPIIb-IIIa (5R01HL132019-07). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10670136. Licensed CC0.

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