# Genetic and therapeutic studies of hemostatic and thrombotic disorders using zebrafish

> **NIH NIH R35** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2022 · $780,000

## Abstract

PROJECT SUMMARY/ABSTRACT
 Pathologic dysregulation of the coagulation system is a major contributor to human morbidity and
mortality, resulting in either excessive bleeding or clotting. Significant progress has been made in the
identification of genetic regulators of the coagulation cascade, but many unknown modifier genes contribute to
the variable disease severity and penetrance observed among patients and families with hemostatic and
thrombotic disorders. Understanding such modifiers could help classify patients at higher risk for pathology as
well as identify novel therapeutic targets. Although major improvements to treatment of hemorrhagic and
bleeding disorders have been made with blood products and human derived or recombinant coagulation
factors, these have limited shelf life and storage conditions, and require intravenous infusion. Anticoagulation
has seen a surge in recent years with many new direct acting oral anticoagulants, but their mechanisms of
action are limited to the coagulation cascade. Building on our previous work, this project will take advantage of
powerful genetic tools, including genome editing nucleases, next generation sequencing, and the zebrafish.
We will conduct a large scale interrogation of the genome to discover hemostasis regulatory genes with the
potential to modify the severity of human coagulation disorders. We have developed a panel of clotting factor
mutant zebrafish using robust genome editing nucleases (TALENS and CRISPR/Cas) and conducted chemical
mutagenesis experiments that have identified potential suppressor mutant lines harboring prospective
thrombosis and hemostasis modifier genes. This panel of mutant fish will also be used for unbiased assays to
identify novel lead molecules that suppress hemorrhage or thrombosis. The approaches described in this
proposal will lead to the identification of the key non-canonical factors regulating hemostasis and
thrombopoiesis, some of which will likely prove to be important genetic modifying factors in humans, or will
suggest novel species-specific but biologically insightful regulatory mechanisms. This will shed light on the
regulatory mechanisms of hemostasis, and the modifiers will also be candidate diagnostic and therapeutic
targets for human thrombotic and hemorrhagic diseases. These targets will be utilized to develop potential
innovative agents and new therapeutic classes for treatment of hemorrhage and thrombosis that could benefit
the general population, as well as patients with bleeding and thrombotic disorders.

## Key facts

- **NIH application ID:** 10375366
- **Project number:** 5R35HL150784-03
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Jordan A. Shavit
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $780,000
- **Award type:** 5
- **Project period:** 2020-04-01 → 2027-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10375366

## Citation

> US National Institutes of Health, RePORTER application 10375366, Genetic and therapeutic studies of hemostatic and thrombotic disorders using zebrafish (5R35HL150784-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10375366. Licensed CC0.

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