# Dissection of the mechanisms underlying sex-influenced cardiovascular disease

> **NIH NIH R01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2020 · $546,000

## Abstract

PROJECT SUMMARY/ABSTRACT
Women are exposed to sex hormones throughout their lifetimes, putting them at significantly higher risk for
cardiovascular disease which is typically pathologic clotting (venous thrombosis/thromboembolism), and
resulting in significant morbidity and mortality. Excessive exposure to estrogens due to sex and gender occurs
with menstruation, endocrine disorders, and exogenous supplementation for contraception, hormone
replacement, and gender transition. Although it is known that sex hormones induce expression of a number of
coagulation factors, the pathways and mechanisms that connect estrogen to the coagulation system, as well
as why there is progression to thrombosis, is poorly understood. Identification of these mediators are central to
any comprehensive understanding of the underlying pathophysiology, could help ascertain patients at higher
risk for thrombosis, and might also pinpoint future therapeutic targets. One of the reasons for the knowledge
gap is the lack of an animal model that develops estrogen-induced thrombosis. We propose to exploit the
powerful genetics of the zebrafish model system to identify the pathways that connect sex hormones to
thromboembolism. This project will leverage highly innovative technologies, including genome editing
nucleases, next generation sequencing, and small molecule analysis in the context of the zebrafish model. In
preliminary studies, we have demonstrated widespread conservation of the coagulation system in zebrafish
and sex hormone induction of thrombosis in embryos and larvae, including fluorescently-tagged and easily
visible estrogen-induced fibrin thrombi. These studies will identify the critical proteins that mediate the link
between sex hormones and coagulation factors. This will result in the rapid development of a candidate panel
of factors that will enhance our understanding of sex hormone-induced thrombosis, and potentially allow
stratification of at risk patients. Novel genes identified will also yield potential therapeutic targets and
preventative strategies, and will inform future translational studies. Pathway analysis using small molecules will
also identify potential therapeutic compounds that might treat or prevent estrogen-induced thrombosis. These
studies will provide insights into the effects of sex and gender on disease, and are aligned with a number of the
objectives in Strategic Goal 1 of the 2019-2023 Trans-NIH Strategic Plan for Women's Health Research,
including investigation of conditions that specifically affect the cardiovascular, menstrual, and gynecologic
health of women.

## Key facts

- **NIH application ID:** 10062572
- **Project number:** 1R01ES032255-01
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Jordan A. Shavit
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $546,000
- **Award type:** 1
- **Project period:** 2020-08-17 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10062572

## Citation

> US National Institutes of Health, RePORTER application 10062572, Dissection of the mechanisms underlying sex-influenced cardiovascular disease (1R01ES032255-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10062572. Licensed CC0.

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