# The Molecular Genetics of Hemostasis

> **NIH NIH R35** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2020 · $579,955

## Abstract

PROJECT SUMMARY
This proposal will continue the longstanding focus of this research program in 3 related areas: 1) the
molecular pathogenesis of disorders in von Willebrand factor (VWF) function, 2) the genetic factors that modify
the manifestations of other inherited bleeding and blood clotting diseases, and 3) regulation of protein transport
from the ER to the Golgi apparatus and its role in the pathogenesis of blood diseases. VWF is a key
component of the blood coagulation system whose deficiency resulting in the most common inherited bleeding
disorder in humans, von Willebrand disease (VWD). Elevated levels of VWF are a major risk factor for
thrombosis, with loss of VWF processing by ADAMTS13 resulting in thrombotic thrombocytopenic purpura
(TTP). This project will exploit recent transformative advances in genomic technology to uncover novel
pathways contributing to the control of VWF and ADAMTS13 function and lay the foundation for a “precision
medicine” approach to these disorders. A novel VWF regulatory gene previously mapped to human
chromosome 2 will be identified through genomic sequence analysis in an additional large cohort of human
subjects and its function explored through modeling by “genome editing” in laboratory mice. Similar tools will
be used to characterize a novel modifier gene for TTP susceptibility mapped to mouse chromosome 5. We will
also assemble a comprehensive dataset for the functional impact of all possible single amino acid substitutions
within the VWF A1 and A2 domains to provide a complete inventory of potential human mutations causing type
2A, 2M and 2B VWD. These data will address the increasingly important clinical problem of “variant of
uncertain significance”, a key challenge for the entire field of human genetics, and should lay the foundation for
eventual diagnosis and subclassification of VWD on the basis of DNA sequence alone, enabling true “precision
medicine”, and serving as a useful paradigm for other genetic diseases. This program will also focus on
identifying novel genes that contribute to venous thromboembolic (VTE) disease susceptibility, both by direct
genomic sequence analysis in human VTE patients, as well as a broad whole genome mutagenesis screen for
thrombosis suppressor genes in laboratory mice. Finally, in a “bedside” to “bench” translation, the lab has
broadened its studies of the rare inherited bleeding disorder, combined deficiency of factors V and VIII, to
explore the basic function of cellular transport pathways leading to unexpected insights into the molecular
pathogenesis of congenital dyserythropoietic anemia II and the regulation of plasma cholesterol levels. These
findings are now circling back from the “bench” to the “bedside”, with the potential to provide improved
diagnosis and therapy for related diseases. Taken together, this research program will apply cutting-edge
genetic and genomic technologies to identify critical genes modifying the risk and severity for a number of
bl...

## Key facts

- **NIH application ID:** 9873999
- **Project number:** 5R35HL135793-04
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** David Ginsburg
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $579,955
- **Award type:** 5
- **Project period:** 2017-03-10 → 2024-02-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9873999

## Citation

> US National Institutes of Health, RePORTER application 9873999, The Molecular Genetics of Hemostasis (5R35HL135793-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9873999. Licensed CC0.

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