# Project 2: Molecular Impact of Carbohydrates on VWF Biology

> **NIH NIH P01** · VERSITI BLOOD HEALTH, INC. · 2020 · $524,919

## Abstract

PROJECT SUMMARY: PROJECT 2
 Type 1 VWD is characterized by a partial quantitative deficiency of VWF. Although it accounts for 70% of
all cases of VWD, the molecular mechanisms underlying the pathogenesis of type 1 VWD remain poorly
understood. However, linkage studies have shown that reduced plasma VWF levels (particularly in patients
with mild to moderate reductions in the range 30 - 50 IU/dL) are independent of the VWF gene on
chromosome 12. Accumulating data from both animal and human studies have demonstrated that the
complex glycan determinants expressed on VWF play critical roles in regulating many aspects of its
biology, including synthesis, proteolysis and clearance. Aim 1 of this project will investigate how VWF N-
and O-glycan structures vary in a large cohort of patients with comprehensively phenotyped VWD already
enrolled through 1) the Zimmerman program, (2) the Canadian type 1 VWD study and (3) the Low VWF
Ireland Cohort study. Given the complex heterogeneous nature of the N- and O- carbohydrate structures
expressed on human VWF, this unique combined clinical resource will for the first time provide adequate
power to enable elucidation of the role of VWF glycans in VWD pathogenesis. In Aim 2, a subset of patients
with type 1 VWD and Low VWF in whom glycan abnormalities have been identified will be selected for
further analysis. In this cohort, the N- and O-glycan structures of VWF will be definitively sequenced using
state-of-the-art mass spectroscopy glycoproteomic analysis. Finally, using a number of novel parallel
strategies, Aim 3 of the project will focus on (1) investigating the mechanisms underlying abnormal VWF
glycosylation in patients with type 1 VWD and Low VWF, and (2) determining whether VWF carbohydrate
modifications play a direct causal role in mediating VWD pathogenesis (e.g. by reducing biosynthesis or
modulating enhanced clearance).

## Key facts

- **NIH application ID:** 9891091
- **Project number:** 5P01HL144457-02
- **Recipient organization:** VERSITI BLOOD HEALTH, INC.
- **Principal Investigator:** James O'Donnell
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $524,919
- **Award type:** 5
- **Project period:** — → —

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9891091

## Citation

> US National Institutes of Health, RePORTER application 9891091, Project 2: Molecular Impact of Carbohydrates on VWF Biology (5P01HL144457-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9891091. Licensed CC0.

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