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Principal Investigator: Neil C Chi
Organization: UNIVERSITY OF CALIFORNIA, SAN DIEGO
Fiscal Year: 2024
Award: $747,916
Funding agency: National Heart Lung and Blood Institute
Project Summary
The heart consists of a multitude of diverse cardiac cell types, including but not limited to cardiomyocytes,
cardiac fibroblasts, epicardial cells, endothelial/endocardial cells and smooth muscle cells, which coordinate to
sustain cardiac function and circulation throughout the body. 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, which is a major leading cause of morbidity and mortality
worldwide. However, what are the specific cell lineages affected during heart failure and how do gene
regulatory networks control genetic programs that direct their pathologic outcomes are key biomedical
questions that remain to be resolved. To address these issues, we have created an interdisciplinary team that
includes physician-scientists who will collect patient heart tissue samples to investigate molecular mechanisms
involved in the pathogenesis of heart failure; genomic and epigenomic experts who will employ cutting-edge
single-cell sequencing and chromatin analysis technologies to examine cell-type specific chromatin
accessibility-interactions and corresponding gene expression; and stem cell biologists who will utilize human
pluripotent stem cell cardiac models and state-of-the-art genome-editing strategies to perform functional
confirmation studies. Through these integrative efforts and analyses, we plan to examine the hypothesis that
cis-regulatory elements and their enhancer-promoter interactions dynamically function and coordinate in a cell-
type specific manner to direct lineage-specific gene expression during cardiac tissue homeostasis, and altering
these highly-regulated cell-type specific cis-regulatory elements and corresponding gene regulatory networks
can lead to heart failure. Specifically, we propose to 1) identify cis-regulatory elements and cell-types that are
affected by heart failure-associated non-coding genetic variants; 2) investigate how gene regulatory networks
controlling specific cardiovascular cell-types are altered during heart failure; and 3) examine how perturbations
of cell-type specific cis-regulatory elements and gene regulatory networks during heart failure impact cell
function and gene expression.
Terms: <ATAC sequencing><ATAC-seq><ATACseq><Address><Affect><Assay for Transposase-Accessible Chromatin using sequencing><Autoregulation><Body Tissues><CRISPR><CRISPR/Cas system><Cardiac><Cardiac Diseases><Cardiac Disorders><Cardiac Muscle Cells><Cardiac Myocytes><Cardiocyte><Cardiovascular><Cardiovascular Body System><Cardiovascular Diseases><Cardiovascular Models><Cardiovascular Organ System><Cardiovascular system><Cell Body><Cell Function><Cell Growth and Maintenance><Cell Lineage><Cell Maintenance><Cell Physiology><Cell Process><Cells><Cellular Function><Cellular Physiology><Cellular Process><Chromatin><Circulation><Clustered Regularly Interspaced Short Palindromic Repeats><Collaborations><Data><Diagnostic><EFRAC><Ejection Fraction><Endothelium><Enhancers><Expression Signature><Fibroblasts><Functional RNA><Gene Expression><Gene Expression Profile><Gene Transcription><Gene variant><Genetic><Genetic Transcription><Genomics><Heart><Heart Diseases><Heart Muscle Cells><Heart Vascular><Heart failure><Heart myocyte><Homeostasis><Human><Leiomyocyte><Letters><Mediating><Modeling><Modern Man><Molecular><Morbidity><Morbidity - disease rate><Non-Coding><Non-Coding RNA><Non-translated RNA><Noncoding RNA><Nontranslated RNA><Nuclear><Outcome><Pathogenesis><Pathologic><Patients><Performance><Physicians><Physiological Homeostasis><Progenitor Cells><RNA Expression><RNA Seq><RNA sequencing><RNAseq><Regulator Genes><Regulatory Element><Scientist><Single cell seq><Smooth Muscle Cells><Smooth Muscle Myocytes><Smooth Muscle Tissue Cell><Subcellular Process><Technology><Tissue Sample><Tissues><Transcription><Transcriptional Regulatory Elements><Treatment Efficacy><Untranslated RNA><Ventricular><allele variant><allelic variant><assay for transposase accessible chromatin followed by sequencing><assay for transposase accessible chromatin seq><assay for transposase accessible chromatin sequencing><assay for transposase-accessible chromatin with sequencing><cardiac failure><cardiac function><cardiomyocyte><cardiovascular disorder><cell behavior><cell type><cellular behavior><circulatory system><customized therapy><customized treatment><epigenomics><function of the heart><gene expression pattern><gene expression signature><gene function><gene regulatory network><genetic variant><genome editing><genomic editing><genomic variant><heart disorder><heart function><human pluripotent stem cell><in vivo><individualized medicine><individualized patient treatment><individualized therapeutic strategy><individualized therapy><individualized treatment><insight><intervention efficacy><mortality><multidisciplinary><noncoding><patient specific therapies><patient specific treatment><programs><promoter><promotor><regulatory gene><response><single cell next generation sequencing><single cell sequencing><stem cells><tailored medical treatment><tailored therapy><tailored treatment><therapeutic efficacy><therapy efficacy><trans acting element><transcriptional profile><transcriptional signature><transcriptome sequencing><transcriptomic sequencing><unique treatment><validation studies>