# Examination of a new mouse model of mitral valve disease

> **NIH NIH R01** · NORTHWESTERN UNIVERSITY · 2023 · $453,849

## Abstract

Project Summary
 Valvular heart disease (VHD), which is most commonly associated with mitral valve prolapse (MVP), causes
severe regurgitation leading to sudden cardiac arrest or sudden cardiac death. Mitral valve endothelial cells
(ECs) are crucial participants in establishing mitral valve structures and are essential for the maintenance of
mitral valve integrity and function. However, the mechanisms by which mitral valve ECs govern structural
changes in the mitral valve during the progression of MVP have yet to be adequately characterized. The long-
term goal of this proposal is to elucidate the fundamental processes that regulate EC function in the integrity and
function of the mitral valve and to understand how the disruption of these mechanisms leads to MVP.
 FOXC1 and FOXC2 are closely related members of the FOX transcription factor family and have numerous
essential roles in cardiovascular development, health, and disease. There is some evidence that human FOXC1
mutations are associated with mitral valve abnormalities, including mitral regurgitation. We have previously
shown that in mice, global homozygous knockout mutations of Foxc1 and/or Foxc2 are associated with vascular
anomalies; however, the mutations also lead to embryonic or perinatal lethality, so attempts to determine how
the two Foxc genes function in adult animals have generally been inconclusive. To overcome this limitation, we
generated a line of mice carrying tamoxifen-inducible, EC-specific, compound Foxc1;Foxc2 mutations (i.e., EC-
Foxc-DKO mice), and the parent award is aimed at elucidating the role of Foxc1/Foxc2 in vascular repair and
intestinal regeneration after injury by directly regulating the expression of CXCL12 and R-spondin 3 paracrine
factors in intestinal ECs. During the course of performing the proposed studies for the parent award using the
Foxc-DKO mice, we also obtained the results from preliminary investigations with these adult mutants, which
indicate that the Foxc1/c2 mutations in the adult impair the structure and integrity of the mitral valve of the heart.
Thus, our central hypothesis is that the transcriptional activity of Foxc1/c2 in mitral valve ECs contributes to mitral
valve integrity and fucntion. We will test our central hypothesis by pursuing the two Specific Aims: (1) To
determine whether Foxc1 and Foxc2 are required in mitral valve ECs for proper development of the mitral valve
and (2) To determine the mechanisms by which EC expression of Foxc1 and Foxc2 regulates the integrity and
function of the mitral valve. In summary, the experiments described in this proposal will provide crucial
information about how Foxc1/c2 deficiency in mitral valve EC populations contributes to mitral valve defects such
as MPV. Furthermore, since impairments in the mitral valve contribute to various cardiac disorders, our findings
may have important implications for other pathologic conditions associated with VHD such as heart failure.

## Key facts

- **NIH application ID:** 10853499
- **Project number:** 3R01HL159976-02S1
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** Tsutomu Kume
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $453,849
- **Award type:** 3
- **Project period:** 2022-04-01 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10853499

## Citation

> US National Institutes of Health, RePORTER application 10853499, Examination of a new mouse model of mitral valve disease (3R01HL159976-02S1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10853499. Licensed CC0.

---

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