# Defining the molecular regulators of valvular delamination via multi-omic dissection of Ebstein’s Anomaly

> **NIH NIH F30** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2021 · $37,830

## Abstract

PROJECT SUMMARY/ABSTRACT
Cardiac valves are critical to the maintenance of unidirectional blood flow in the heart. Congenital and acquired
valvulopathies are a major source of morbidity and mortality in both the pediatric and adult populations. Current
therapeutic strategies are limited, often requiring surgical replacement with suboptimal prostheses.
Valvulogenesis begins with formation of the endocardial cushions via epithelial-to-mesenchymal transition
(EMT). Many of the signaling pathways regulating this EMT event have been defined; however, little is known
about the molecular regulators of post-EMT valvulogenesis. Ebstein’s Anomaly, a rare congenital heart defect,
is characterized by variably dysplastic, muscularized tricuspid valve leaflets that are often tethered to the
underlying myocardium, resulting in apical displacement of the annulus and atrialization of the right ventricle.
This defect is often attributed to a failure of valvular delamination – a critical morphogenetic step of post-EMT
valvulogenesis during which the primordial valve leaflets separate from the underlying myocardium. Previous
studies suggest that altered differentiation dynamics of valvular interstitial cells (VICs) may contribute to the
pathogenesis of this valvular defect. I propose to define the molecular regulators of valvular delamination
via a multi-omic dissection of Ebstein’s Anomaly, leveraging an Ebstein’s Anomaly murine model system,
primary human tissue, and human genetics data. In my first aim, I will use spatiotemporal single cell RNA
sequencing and human genetics analyses to identify the atrioventricular cushion signaling interactions regulating
valvular delamination. In my second aim, I will use an integrated single cell RNA/ATAC sequencing approach to
define the gene regulatory networks driving VIC fate determination. My primary sponsor, Dr. Deepak Srivastava,
has extensive expertise in developmental cardiac biology, human genetics, and stem cell biology. My co-
sponsor, Dr. Chun (Jimmie) Ye, has an expertise in experimental and computational single cell genomics. Their
collective expertise will assure that I receive the necessary training and mentorship to complete the proposed
research. To obtain the rare tissue samples required for my project, I have formed a multi-center collaboration
with two high volume Ebstein’s Anomaly patient centers. Additionally, I have secured expertise in human
genetics and machine learning from Dr. Jingjing Li, Ph.D., in support of the human genetics component of my
project. Concurrently, I am engaging in a longitudinal clinical preceptorship in pediatric cardiothoracic surgery
with my clinical training co-sponsor, Dr. Peter Kouretas, Surgical Director of the UCSF Pediatric Heart
Transplantation Program. Overall, the proposed research will elucidate previously uncharacterized mechanisms
of late atrioventricular valvular morphogenesis and inform future efforts toward the development of novel
regenerative-medicine based t...

## Key facts

- **NIH application ID:** 10233685
- **Project number:** 1F30HL158170-01
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** ALEXANDER Flaherty MERRIMAN
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $37,830
- **Award type:** 1
- **Project period:** 2021-04-01 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10233685

## Citation

> US National Institutes of Health, RePORTER application 10233685, Defining the molecular regulators of valvular delamination via multi-omic dissection of Ebstein’s Anomaly (1F30HL158170-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10233685. Licensed CC0.

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