# Cardiac Lineage-Specific Molecular Mechanisms of Heart Failure

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2023 · $636,285

## Abstract

Project Summary
The heart consists of a multitude of diverse cardiac cell types that form cardiac structures critical for
maintaining heart function. These cell populations include not only cardiomyocytes, cardiac fibroblasts,
epicardial cells, endothelial/endocardial cells and smooth muscle cells, but also more specialized cell types
comprising the cardiac valves, cardiac conduction system, etc. Thus, regulated maintenance of these cell
types is crucial for optimal heart performance, and disrupting the function of specific cell lineages can result in
distinct heart diseases including heart failure (HF), which is a major leading cause of morbidity and mortality
worldwide. However, what are the specific cell lineages affected during HF and how do gene regulatory
networks (GRNs) control genetic programs that direct their pathologic outcomes are key biomedical questions
that we seek to address in our parent R01HL156576 grant. Toward this end, this grant proposal has mainly
focused on analyzing the cardiac chambers (i.e., ventricles and atria) but not cardiac valves, which can be
defective and diseased in HF and in some cases can be the cause of HF. Thus, to expand our efforts and
examine all cell-types participating in failing and non-failing human hearts in vivo including the cardiac valves,
we propose to implement joint single cell/nuclear (sc/sn) RNA-seq and ATAC-seq technologies (i.e., single cell
multi-omics) on not only the cardiac chambers as originally proposed in our parent grant but also the cardiac
valves, particularly mitral valve, in response to the Notice of Special Interest (NOSI): Administrative
Supplements to Encourage Research in Valvular Heart Disease (CAROL Act, NOT-HL-23-078). In addition to
identifying distinct CV cell-types and their related transcriptional profiles and chromatin landscape, we further
seek to elucidate the interactions between cell-type specific cis-regulatory elements (CREs), which mediate the
GRNs that control how CREs direct gene expression of these cell types in the cardiac (mitral) valves of failing
and non-failing hearts. Furthermore, because the structural form of the cardiac valve is critical for regulating its
function, we propose to further investigate the spatial organization of identified cell types in the cardiac valves,
particularly mitral valves, of human hearts with and without heart failure and cardiac valve defects/disease.
Thus, the overall goal of this supplement to our original parent grant is to generate single-cell multi-omics and
spatial imaging data of cardiac valves, particularly mitral valves, from a large, well-phenotyped cohort of
patients with and without heart failure and mitral valve defects/disease. We will then create comprehensive
maps of cell-type specific gene regulation including integrated genomic profiles and spatial localization of all
cells and cis-regulatory programs in each cell type.

## Key facts

- **NIH application ID:** 10852685
- **Project number:** 3R01HL156576-03S1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** Neil C Chi
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $636,285
- **Award type:** 3
- **Project period:** 2021-02-01 → 2025-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10852685

## Citation

> US National Institutes of Health, RePORTER application 10852685, Cardiac Lineage-Specific Molecular Mechanisms of Heart Failure (3R01HL156576-03S1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10852685. Licensed CC0.

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