# Regulators of von Willebrand Factor Levels

> **NIH NIH R01** · UNIVERSITY OF NORTH TEXAS · 2022 · $297,000

## Abstract

ABSTRACT
Von Willebrand Factor (VWF) is a multimeric glycoprotein that acts as an adhesive in the
subendothelium to the platelets at the injury site and stabilizes factor VIII in the plasma. Deficiency of
VWF results in von Willebrand disease (VWD), which is the most prevalent inherited bleeding disorder
in humans. Many mutations in the VWF gene causing VWD have been characterized. Despite this
progress in genetic studies on VWD, only limited information is available on modifier genes that cause
type I VWD, where the patients have considerably lower VWF levels. Similarly, individuals with high
VWF levels are at risk for thrombosis. Thus, there is a gap in the knowledge of the genes involved in
regulating the levels of VWF. Identification of modifiers/regulators that explain the molecular basis for
type 1 VWD is needed for understanding the mechanisms of type 1 VWD. Likewise, regulatory genes
for high VWF levels might help alleviate the thrombotic episodes. We have recently created the
zebrafish VWD model to identify genes by functional knockdowns of various genes using heterozygote
VWD fish. The most important advantage of the zebrafish for this proposal is its amenability to rapidly
screen for genes using the piggyback knockdown method developed in our laboratory for the regulatory
genes that modifier control the VWF levels. This screening should provide us with the list of the
regulatory genes that would have been functionally validated in zebrafish. These results should be
useful in sequencing the corresponding genes from patients with type I VWD. They should also
complement the whole genome sequencing efforts of type I VWD patients in taking a first look at the
sequences corresponding to genes identified in the above zebrafish screening. Similarly, these results
will be useful in counseling for the risk of thrombosis. Our goal in this proposal will be to identify novel
factors that control the levels of the VWF.
To identify novel genes involved in modifying the levels of Vwf, we propose one specific aim. In this
aim, we will establish a screening protocol for identifying Vwf modifier genes in zebrafish by assaying
for the Vwf levels by ELISA. Subsequently, we will knockdown a known gene that is already found as a
modifier gene for VWF in humans and confirm the assay's utility in screening for the genes controlling
human VWF levels. Then we will comprehensively perform genome-wide knockdowns of genes that
may regulate the Vwf levels in zebrafish. The results from this aim will identify the hitherto unknown
factor(s) that regulate the Vwf levels. We will also generate mutant zebrafish for selected genes to
pursue structure-function studies. The above identification of modifier genes in zebrafish will be useful
as candidate genes causing the type I VWD and high VWF levels. Furthermore, the genome-wide
knockdown strategies developed here will provide an approach to study other physiological pathways.

## Key facts

- **NIH application ID:** 10459587
- **Project number:** 5R01HL159399-02
- **Recipient organization:** UNIVERSITY OF NORTH TEXAS
- **Principal Investigator:** PUDUR JAGADEESWARAN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $297,000
- **Award type:** 5
- **Project period:** 2021-08-01 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10459587

## Citation

> US National Institutes of Health, RePORTER application 10459587, Regulators of von Willebrand Factor Levels (5R01HL159399-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10459587. Licensed CC0.

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