# GPIb-IX and VWF in thrombosis and thrombocytopenia

> **NIH NIH R35** · EMORY UNIVERSITY · 2023 · $1,095,500

## Abstract

PROJECT SUMMARY
Understanding the interplay between blood, vessel, and shear flow is key to elucidate the pathophysiology
of thrombosis and related diseases. Both glycoprotein (GP)Ib-IX-V complex, an abundant receptor
complex on the platelet surface, and its ligand von Willebrand factor (VWF) in the plasma critically mediate
hemostasis, thrombosis, and thrombo-inflammation by sensing and responding to blood shear flow.
Although much is known about this important receptor-ligand pair, significant knowledge gaps, especially
the molecular mechanisms underlying their activation and regulation, have remained open. As the
continuation of two current R01 grants entitled “Structure and function of platelet glycoprotein Ib-IX-V
complex” and “Conformational activation of von Willebrand factor”, this proposed R35 project seeks to fill
several long-standing knowledge gaps and address controversial questions in our understanding of GPIb-
IX-V, VWF and related disease pathology. Through systematic, multidisciplinary analysis of inter-domain
interactions in GPIb-IX and VWF, we have recently identified the mechanosensory domain (MSD) in GPIb-
IX and the discontinuous autoinhibitory module (AIM) in VWF, leading to elucidation of their respective
activation mechanisms. In addition to significant implications on pathophysiology of many related
thrombotic and thrombocytopenic disorders, these mechanisms provide a coherent conceptual framework
for future mechanistic investigations and novel therapeutic development. In this project, we seek to
determine the structure of the GPIb-IX complex and VWF domains, resolve the current controversy about
the activation mechanism of VWF particularly the AIM conformation, and elucidate mechanisms that
regulate activities of GPIb-IX and VWF. To accomplish these goals, we will continue to develop new
reagents targeting a key domain, new constructs enabling interdisciplinary analysis, and new mouse
strains bearing key mutations to specifically modulate their activity. The seven-year funding period will
provide additional flexibility and continuity for pursuing difficult-to-get structures and developing key
reagents. Overall, completion of the proposed study will elucidate the fundamental activation and
regulation mechanisms of GPIb-IX-V and VWF, significantly advance our understanding of pathogenesis
of many thrombotic and thrombocytopenic diseases, and potentially identify new strategies to develop
treatments for these diseases.

## Key facts

- **NIH application ID:** 10574144
- **Project number:** 1R35HL166654-01
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** Renhao Li
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $1,095,500
- **Award type:** 1
- **Project period:** 2023-05-15 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10574144

## Citation

> US National Institutes of Health, RePORTER application 10574144, GPIb-IX and VWF in thrombosis and thrombocytopenia (1R35HL166654-01). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10574144. Licensed CC0.

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