# Mechanisms underlying myxomatous valve disease

> **NIH NIH R01** · CINCINNATI CHILDRENS HOSP MED CTR · 2021 · $546,559

## Abstract

Project Summary/Abstract
Myxomatous degeneration leads to mitral valve prolapse, which occurs in almost 3% of the general population
and 10% of the elderly, is a significant cause of morbidity and mortality. Additionally, early-onset of myxomatous
mitral valve degeneration is associated with both syndromic and non-syndromic diseases, supporting there is an
underlying genetic etiology. Despite the frequency of mitral valve diseases, the cellular, molecular, and genetic
etiologies underlying myxomatous degeneration of the mitral valves remain poorly understood. Presently, valve
reconstruction and replacement surgeries are the only therapies available for mitral valve diseases. Thus, in
order to develop novel non-invasive pharmacological therapies that can effectively prevent and ameliorate mitral
valve diseases, it is essential to understand conserved mechanisms the underlie the progression of valve
diseases in vertebrates. The specific aims of this proposal are to interrogate the mechanisms by which loss of
the Nr2f transcription factors can lead to the development of myxomatous valves in zebrafish and mice.
Numerous studies have indicated that mutations in Nr2f genes in humans are associated with a spectrum of
congenital heart defects, some of which are correlated with myxomatous valve degeneration. While requirements
for Nr2f factors are well-established in heart development, previous work has not implicated Nr2f transcription
factors in homeostasis of mature valves and myxomatous valve degeneration. Interestingly, the majority of
previous genes associated with myxomatous valve degeneration are involved in the regulation of extracellular
matrix, mechanotransduction, and cilia. Our preliminary analysis in adult zebrafish mutants called acorn worm
(aco), which are deficient for Nr2f1a, show they develop myxomatous atrioventricular valves with all the hallmarks
of myxomatous valves in mammals. Furthermore, we identify Nr2f proteins are expressed in previously
unrecognized populations of cells within the atrioventricular valves. In Aim 1, we will use tissue-specific rescue
and knockout approaches in zebrafish and mice to determine if valve endothelial cells require Nr2f to maintain
valve homeostasis and prevent myxomatous generation. In Aim 2, we will employ pharmacological and genetic
epistasis to decipher if RA and signals including Fibrillin 1, whose misexpression is associated with myxomatous
degeneration in humans, function downstream of Nr2f1a to promote myxomatous atrioventricular valve
degeneration. In Aim 3, we will use lineage tracing and ablation studies to determine if specific immune cells
contribute to the progression of myxomatous atrioventricular valves in aco mutants. Our use of these unique
mutants with complementary analysis in mice will dramatically improve our understanding of conserved
mechanisms that can lead to the progression of myxomatous valve degeneration in vertebrates. Ultimately, our
studies may provide the foundation ...

## Key facts

- **NIH application ID:** 10312919
- **Project number:** 1R01HL154522-01A1
- **Recipient organization:** CINCINNATI CHILDRENS HOSP MED CTR
- **Principal Investigator:** Joshua Waxman
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $546,559
- **Award type:** 1
- **Project period:** 2021-08-01 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10312919

## Citation

> US National Institutes of Health, RePORTER application 10312919, Mechanisms underlying myxomatous valve disease (1R01HL154522-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10312919. Licensed CC0.

---

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