# Project 4: Epigenetic Mechanisms Modulating VWF

> **NIH NIH P01** · VERSITI BLOOD HEALTH, INC. · 2021 · $302,922

## Abstract

PROJECT SUMMARY: PROJECT 4 (ESI)
Von Willebrand factor (VWF) is an essential hemostatic protein and alterations of VWF levels are associated
with bleeding and thrombosis. VWF levels < 50 IU/dL represent a risk factor for bleeding while VWF levels < 30
IU/dL define Willebrand disease (VWD) and are often associated with mutations in the VWF gene.
Alternatively, high levels of VWF are associated with thrombotic conditions such as myocardial infarction and
stroke. The wide distribution of VWF levels in the general population indicates that there are multiple factors
that regulate VWF levels. To date, major modifiers such as the ABO blood group and specific variants in genes
implicated in VWF release (STXBP1, GNA12) or clearance (LRP1, AVPR2, ACE) account for only 30-40% of
the known variation. The objective of this proposal is to identify alternative mechanisms that regulate VWF
levels. Our central hypothesis is that specific transcriptional and epigenetic mechanisms in endothelial
cells are critical determinants of VWF levels. The hypothesis is based on recent reports and our preliminary
data that microRNAs levels (miRs), transcription factors, and epigenetic mechanisms can all modify VWF
levels. We are uniquely positioned to test this hypothesis using our primary patient-derived blood outgrowth
endothelial cells (BOECs) that replicate accurately the disease phenotype. We will test our hypothesis via the
following three aims, (1) Determination of transcriptional mechanisms that affect VWF expression in BOECs,
(2) Determination of the contribution of methylation and histone-acetylation status of VWF on VWF expression
from BOECs and (3) Determination of the role of transcriptional and epigenetic mechanisms on VWF levels in
aging. Our preliminary data and our expertise in BOEC models positions us well to carry out these proposed
research aims. Successful completion of these aims will (1) confirm novel transcriptional regulators of VWF in
low VWF BOECs, such as miR-24 and TCF4, (2) confirm the regulatory role of epigenetic modifiers, such as
VWF promoter methylation and histone acetylation, in determining VWF levels, and (3) demonstrate novel
transcriptional and epigenetic regulation that may explain the effects of aging on VWF levels. In addition, our
un-biased RNA sequencing, methylation arrays, and microRNA arrays may also identify additional targets for
VWF regulation. Globally, by evaluating the role of transcriptional and epigenetic regulators on VWF levels it is
anticipated that we will identify novel mechanisms of VWF expression and function. Such results are significant
as they are expected to advance the understanding of how modifiers outside of the VWF coding region can
influence VWF levels and represent novel pathways of VWF regulation that have previously not been well
examined.

## Key facts

- **NIH application ID:** 10113379
- **Project number:** 5P01HL144457-03
- **Recipient organization:** VERSITI BLOOD HEALTH, INC.
- **Principal Investigator:** Christopher Ng
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $302,922
- **Award type:** 5
- **Project period:** 2019-03-15 → 2024-02-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10113379

## Citation

> US National Institutes of Health, RePORTER application 10113379, Project 4: Epigenetic Mechanisms Modulating VWF (5P01HL144457-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10113379. Licensed CC0.

---

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