# Investigation of the Cellular and Molecular Mechanisms of Thrombocyte Integrin Signaling

> **NIH NIH R01** · BAYLOR COLLEGE OF MEDICINE · 2022 · $411,600

## Abstract

Abstract
 Platelet integrin αIIbβ3 is central to platelet activation, which occurs through highly complex molecular
interactions and structural alteration. Ultimately, αIIbβ3 matures its affinity for fibrinogen and von Willebrand
factor. Dysregulation in αIIbβ3 affinity maturation events causes Glanzmann's thrombasthenia or
thrombocytopenia. Therefore, fine-tuning these interactions through the αIIbβ3 receptor is a proven and effective
strategy for both therapeutic thrombotic pathology targeting and immunotherapy. Currently, there are no αIIbβ3
inhibitors for long-term clinical use, while current inhibitors for short-term use may cause serious
thrombocytopenia. The overall goal of our proposed research is to understand the molecular basis of the αIIbβ3
shapeshifting and the mechanochemistry of αIIbβ3 activation and inhibition by small molecules, including clinical-
drugs. Our guiding hypothesis is that multiple forms of αIIbβ3 exist in a dynamic conformational equilibrium that
is temporally and spatially regulated by cell signaling, association with the cytoskeleton, and interactions with
exocellular ligands. We will determine, for the first time, the single-particle cryoEM structure of intact αIIbβ3,
characterize structural transitions at the atomic level as they relate to physiological ligands (e.g., fibrinogen), and
determine the effects of clinically relevant antagonists on αIIbβ3 conformational equilibrium both in situ and in
vitro. All specific aims will elaborate integrin αIIbβ3 events at the molecular level pertaining to these objectives.
Aim 1 experiments will characterize shapeshifting structural changes of αIIbβ3 induced by ligands or clinical-
relevant drugs. We will investigate the kinetics of the conformational dynamics of the purified full-length αIIbβ3
using a single-particle cryoEM approach and wide-ranging biochemical techniques for the protein in solution.
Aim 2 experiments will study architectural changes in intact αIIbβ3 by probing its conformational states on the
cell surfaces using conformation-reporting mAbs and by directly solving in situ structures using cutting-edge
advanced cryoET imaging techniques. Collectively, our proposed studies will provide unique molecular insights
into structural and bidirectional signaling regulation of αIIbβ3, which will advance our understanding of integrin
biology and may identify new antagonists for modulating αIIbβ3 function.

## Key facts

- **NIH application ID:** 10421216
- **Project number:** 1R01HL162842-01
- **Recipient organization:** BAYLOR COLLEGE OF MEDICINE
- **Principal Investigator:** Zhao Wang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $411,600
- **Award type:** 1
- **Project period:** 2022-05-05 → 2026-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10421216

## Citation

> US National Institutes of Health, RePORTER application 10421216, Investigation of the Cellular and Molecular Mechanisms of Thrombocyte Integrin Signaling (1R01HL162842-01). Retrieved via AI Analytics 2026-05-29 from https://api.ai-analytics.org/grant/nih/10421216. Licensed CC0.

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