# Mechanisms and Therapeutics for Congenital Aortic Valve Disease

> **NIH NIH R01** · RESEARCH INST NATIONWIDE CHILDREN'S HOSP · 2024 · $664,824

## Abstract

Abstract
 Diseases affecting the heart valves are among the most common type of cardiovascular medical
condition affecting 2.5% of the population in the United States. The aortic valve is the most often affected and
encompasses both congenital and acquired forms. Congenital aortic valve disease is the result of a malformed
valve and represents the most common type of congenital heart defect when including bicuspid aortic valve
(BAV), which has a prevalence of 1-2% in the population. At birth, diseased aortic valves are often myxomatous
with bicuspid valve morphology and display congenital aortic valve stenosis (AVS). If untreated, congenital AVS
results in progressive left ventricular hypertrophy and ultimately heart failure. Severe congenital AVS is treated
with surgical or catheter-based valve intervention or replacement. Accordingly, there is a critical need for
pharmacologic therapies for AVS that will obviate the need for surgical intervention. We were the first to discover
that pathogenic variants in NOTCH1 were associated with BAV and AVS in humans, and we subsequently found
that Notch1 signaling is critical for heart valve development in murine models. Furthermore, our prior publications
have demonstrated a genetic and molecular link between Notch1 and nitric oxide (NO) signaling. We and others
also found pathogenic variation in GATA5, a zinc finger transcription factor, was associated with BAV in humans.
Interestingly, Gata5-null mice display BAV and decreased expression of Nos3 and Notch signaling in the
embryonic heart. These findings support the prevailing view about the critical roles of NOTCH1, GATA5, and
NOS3 in the pathogenesis of human BAV and congenital AVS. We recently generated Notch1 and Gata5
compound mutant mice (Notch1+/-;Gata5-/-); these mice display highly penetrant congenital AVS and survive to
adulthood with progressive aortic valve stenosis. This exciting, new murine model recapitulates the human
disease condition and will allow us to decipher the mechanisms of disease development and progression. The
long-term goal of this research is to understand how molecular pathways regulated by NOTCH1, GATA5, and
NOS3 in the aortic valve can be manipulated to treat congenital AVS and progressive valve stenosis. The
objectives are to utilize this new highly penetrant and clinically relevant congenital AVS mouse model for the
discovery and testing of mechanism-based pharmacologic therapies. We will achieve this in the following aims:
Specific Aim 1. To define the cell-type specific molecular pathways underlying development of
congenital AVS using the Notch1;Gata5 compound mutant mouse model. Specific Aim 2. To determine the
cellular and molecular mechanisms for disease progression in congenital AVS using the Notch1;Gata5 mutant
mouse model. Specific Aim 3. To test novel therapeutics for congenital AVS and stenotic disease progression.

## Key facts

- **NIH application ID:** 10996250
- **Project number:** 1R01HL175924-01
- **Recipient organization:** RESEARCH INST NATIONWIDE CHILDREN'S HOSP
- **Principal Investigator:** Vidu Garg
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $664,824
- **Award type:** 1
- **Project period:** 2024-07-05 → 2028-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10996250

## Citation

> US National Institutes of Health, RePORTER application 10996250, Mechanisms and Therapeutics for Congenital Aortic Valve Disease (1R01HL175924-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10996250. Licensed CC0.

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