# Genomic structural dynamics in fibroblasts during heart failure

> **NIH NIH F32** · UNIVERSITY OF CALIFORNIA LOS ANGELES · 2022 · $72,302

## Abstract

ABSTRACT
Heart failure is a debilitating syndrome that results in depletion of oxygen and nutrients in critical organs for
survival and is associated with left ventricular dysfunction and deposition of scar tissue by fibroblasts. Although
genetic mutations partially explain the etiology of phenotypic dysfunction in the heart, disease gene expression
programs and organ-level pathology are routinely observed in patients with no family history of heart failure. At
a global level, chromatin is organized into: higher order regions that interact with themselves more than with
others, so-called topologically associating domains (TADs); active and inactive compartments that tend to
contain regions of higher or lower transcription, respectively; and chromosome territories. Cardiac chromatin
structure is deranged with heart failure, as measured by high-throughput chromatin conformation capture (Hi-C).
In addition, chromatin architecture plays a role in conferring cell-type specific transcriptomes and 3D modeling
of Hi-C contacts into populations of structures reveals differential rules for cell-type specific gene positioning and
genome compartmentalization. A major gap in our understanding is the relationship between local and long
range chromatin interactions in conferring disease specific global nuclear structure. To this end, we propose
defining 3D chromatin architectural dynamics with fibroblast disease, to reveal how disease gene expression
paradigms are driven with pathological stimulus. In Aim 1 we will use high-throughput sequencing and
computational modeling to generate integrated 3D models of healthy and activated fibroblast genomes to
understand spatial relationships between genomic regulatory regions in disease. Because modeling generates
a population of structures, we can model how structural changes in a population of nuclei contribute to organ
level response, and how classes of genes undergo coordinated actions in 3D. In Aim 2 we will advance these
genomic models by validating findings with orthogonal techniques. We will perform 3D FISH on candidate genes
from our models to confirm these spatial changes in vivo with pressure overload mediated heart failure. In
isolated fibroblasts, we will perform gain and loss of function studies on these genes to mechanistically link their
chromatin structure, transcription, and phenotype. This project will have long-term basic and translational
impacts, with the end goal of shaping the Applicant into an independent scientist within 3 years.

## Key facts

- **NIH application ID:** 10466412
- **Project number:** 1F32HL160099-01A1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA LOS ANGELES
- **Principal Investigator:** Douglas Joseph Chapski
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $72,302
- **Award type:** 1
- **Project period:** 2022-07-01 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10466412

## Citation

> US National Institutes of Health, RePORTER application 10466412, Genomic structural dynamics in fibroblasts during heart failure (1F32HL160099-01A1). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10466412. Licensed CC0.

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