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Cardiac Lineage-Specific Molecular Mechanisms of Heart Failure

心力衰竭的心脏谱系特异性分子机制

基本信息

批准号：
10152319
负责人：
Neil C Chi
金额：
$ 76.53万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-02-01 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10152319
关键词：
ATAC-seq Address Affect Blood Circulation Cardiac Cardiac Myocytes Cardiovascular Diseases Cardiovascular Models Cardiovascular system Cell Lineage Cell Maintenance Cell physiology Cells Chromatin Clustered Regularly Interspaced Short Palindromic Repeats Data Diagnostic EFRAC Endothelium Enhancers Fibroblasts Gene Expression Gene Expression Profile Genetic Genetic Transcription Genomics Heart Heart Diseases Heart failure Homeostasis Human Lead Letters Mediating Modeling Molecular Morbidity - disease rate Nuclear RNA Outcome Pathogenesis Pathologic Patients Performance Physicians Regulator Genes Regulatory Element Scientist Smooth Muscle Myocytes Technology Tissue Sample Tissues Treatment Efficacy Untranslated RNA Ventricular cell behavior cell type epigenomics gene function genetic variant genome editing heart function human pluripotent stem cell in vivo individualized medicine insight mortality multidisciplinary programs promoter response single cell sequencing stem cells transcriptome sequencing validation studies

项目摘要

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.

项目总结