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：
10337287
负责人：
Neil C Chi
金额：
$ 76.63万
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/10337287
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 gene regulatory network 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.

项目摘要心脏由多种不同的心脏细胞类型组成，包括但不限于心肌细胞，心脏成纤维细胞，心外膜细胞，内皮/心内膜细胞和平滑肌细胞，它们协调至维持整个身体的心脏功能和循环。因此，调节这些细胞类型的维护对于最佳心脏表现和破坏特定细胞谱系的功能至关重要包括心力衰竭在内的心脏病，这是发病率和死亡率的主要主要原因全世界。但是，在心力衰竭期间受影响的特定细胞谱系以及基因如何监管网络控制指导其病理结果的遗传程序是关键的生物医学尚待解决的问题。为了解决这些问题，我们创建了一个跨学科团队包括医师科学家，他们将收集患者心脏组织样本以研究分子机制参与心力衰竭的发病机理；基因组和表观基因组专家，他们将采用尖端单细胞测序和染色质分析技术，以检查细胞类型特异性染色质可及性相互作用和相应的基因表达；和将使用人类的干细胞生物学家多能干细胞心脏模型和最先进的基因组编辑策略以执行功能确认研究。通过这些综合努力和分析，我们计划研究以下假设。顺式调节元件及其增强子促进剂相互作用动态起作用并在细胞中坐标在心脏组织稳态期间类型特定方式以直接直接谱系特异性基因表达和改变这些高度调节的细胞类型特异性顺式调节元件和相应的基因调节网络会导致心力衰竭。具体而言，我们建议1）确定顺式调节元素和细胞类型受心力衰竭相关的非编码遗传变异的影响； 2）研究基因调节网络如何在心力衰竭期间，控制特定的心血管细胞类型会改变； 3）检查如何扰动心力衰竭冲击细胞期间细胞类型的特异性顺式调节元件和基因调节网络功能和基因表达。