# The Molecular Genetics of Hemostasis

> **NIH NIH R35** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2024 · $941,106

## Abstract

PROJECT SUMMARY
 Our research program centers on the regulation of hemostasis and thrombosis, heavily informed by the
study of human patients with associated genetic disorders. The current proposal will continue this work, with a
specific focus in four areas: 1) characterization of endothelial cell heterogeneity across diverse vascular beds
and its role in the pathogenesis of thrombotic thrombocytopenic purpura (TTP), hemolytic uremic syndrome, and
other vascular disorders, 2) application of comprehensive deep mutational scanning methods, using von
Willebrand factor (VWF) and plasminogen activator inhibitor-1 (PAI-1) as model hemostasis proteins, to guide
precision medicine genome sequence interpretation, 3) directed molecular evolution of novel serine protease
inhibitor (SERPIN) proteins with unique new properties, providing valuable insight into protein structure/function
relationships as well as identifying potential novel therapeutics, and 4) characterization of the full cargo
repertoires for the LMAN1 and SURF4 cargo receptors, identifying potential overlapping cargo receptors, and
probing unconventional protein secretion, with important implications for disorders of hemostasis and lipid
metabolism. We will identify and characterize a novel modifier gene for TTP susceptibility in the mouse, with
potential relevance for the variable presentation of TTP in humans. We will also characterize endothelial gene
expression across diverse vascular beds in vivo at the single cell level in mouse models for TTP and other
vascular disorders. Building on our past work, we will assemble complete datasets encompassing every possible
single amino acid substitution within PAI-1 and select domains of VWF to markedly improve the diagnosis of
human disorders due to inherited mutations in these genes and interpretation of clinical genome sequencing
data. These data will also provide a powerful resource for exploring structure–function relationships within these
proteins. We will also apply these approaches to probe the determinants of target protease specificity for PAI-1
and related members of the SERPIN gene family, with the potential to enable the development of novel
therapeutic reagents for the treatment of hemostatic and other human diseases. Finally, we will continue our
studies of the ER to Golgi cargo receptors, LMAN1/MCFD2, required for efficient secretion of coagulation factors
V and VIII, and SURF4, the cargo receptor for PCSK9 and other proteins regulating plasma cholesterol, to
identify the full repertoire of cargo for each receptor, as well as potential overlapping cargo receptors, with
important implications for patients with associated genetic disorders, as well as the development of future novel
therapeutics.

## Key facts

- **NIH application ID:** 10786263
- **Project number:** 1R35HL171421-01
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** David Ginsburg
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $941,106
- **Award type:** 1
- **Project period:** 2024-03-01 → 2031-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10786263

## Citation

> US National Institutes of Health, RePORTER application 10786263, The Molecular Genetics of Hemostasis (1R35HL171421-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10786263. Licensed CC0.

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