# Mechanical regulation of von Willebrand factor

> **NIH NIH R01** · LEHIGH UNIVERSITY · 2021 · $606,912

## Abstract

PROJECT SUMMARY/ABSTRACT
In human bodies, bleeding is stopped when a clot is formed at the site of vascular damage. Under rapid flow
conditions, the plasma protein von Willebrand factor (VWF) plays an indispensable role in capturing both
platelets and collagen on damaged vessel walls, allowing the formation of platelet plugs. The adhesion between
VWF and platelets is mediated by the interaction between the A1 domain of VWF and the Ib chain of the
platelet receptor GPIb-IX complex. Gain-of-function mutations in A1 that enhance this interaction lead to type
2B von Willebrand disease (VWD). Targeting the A1GPIb-IX interaction has been an emerging strategy to treat
or preempt bleeding and thrombotic disorders, though success in this area has been very limited. The lack of
progress is due largely to the enigmatic nature of how exactly A1 remains inactive in blood circulation and how it
is instantly activated to bind to GPIb-IX upon bleeding. Our recent identification of an autoinhibitory module
(AIM), consisting of N- and C-terminal flanking regions on A1 and their O-linked glycans, is crucial for
understanding A1 mechanoactivation during bleeding. In addition, AIM can be unfolded by a tensile pulling force
of 8 to 20 pN. Based on these preliminary discoveries, we hypothesize that O-linked glycan structures,
particularly sialic acids, further stabilize AIM and contribute to the mechanical regulation of A1GPIb-IX binding
and that modulating AIM’s mechanical properties can be utilized to treat or preempt blood diseases. We propose
to test this potentially paradigm-shifting hypothesis using state-of-the-art analytical biophysical tools, including
single-molecule force spectroscopy, single-molecule fluorescence microscopy and all-atom molecular
dynamics simulation. Three specific aims will be pursued to test the hypotheses. Aim 1 is to characterize the
structure and biomechanical properties of AIM. Aim 2 is to determine how autoinhibition is regulated by O-linked
glycosylation in AIM. And Aim 3 is to investigate the role of AIM in type 2B VWD and therapeutic applications.
Completion of the proposed studies will identify the key molecular and biophysical mechanisms underlying how
AIM mechanically regulates VWF function and platelet binding and will aid in devising novel therapeutic
strategies for the prevention and treatment of human blood disease.

## Key facts

- **NIH application ID:** 10296176
- **Project number:** 1R01HL153986-01A1
- **Recipient organization:** LEHIGH UNIVERSITY
- **Principal Investigator:** Xiaohui Frank Zhang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $606,912
- **Award type:** 1
- **Project period:** 2021-09-01 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10296176

## Citation

> US National Institutes of Health, RePORTER application 10296176, Mechanical regulation of von Willebrand factor (1R01HL153986-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10296176. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*