Cardiac Lineage-Specific Molecular Mechanisms of Heart Failure

项目摘要 心脏由多种不同类型的心肌细胞组成，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 维持心脏功能和全身循环。因此，这些细胞类型的受控维护 对最佳心脏功能至关重要，而干扰特定细胞系的功能会导致不同的 心脏病，包括心力衰竭，这是导致发病率和死亡率的主要原因 全世界。然而，在心力衰竭过程中受影响的特定细胞系是什么？基因是如何影响的 调控网络控制基因程序，指导他们的病理结果是关键的生物医学 有待解决的问题。为了解决这些问题，我们成立了一个跨学科团队， 包括将收集患者心脏组织样本以研究分子机制的内科科学家 参与心力衰竭的发病机制；基因组和表观基因组学专家将使用尖端技术 单细胞测序和染色质分析技术检测细胞类型特异性染色质 可获得性-相互作用和相应的基因表达；干细胞生物学家将利用人类 多能干细胞心脏模型和最先进的基因组编辑策略 验证性研究。通过这些综合努力和分析，我们计划检验以下假设 顺式调控元件及其增强子-启动子相互作用在细胞中动态发挥作用和协调。 在心脏组织动态平衡和改变期间，以类型特定的方式指导谱系特定的基因表达 这些高度调控的细胞类型的特定顺式调控元件和相应的基因调控网络 会导致心力衰竭。具体地说，我们建议1)确定顺式调节元件和细胞类型 受心力衰竭相关的非编码遗传变异的影响；2)研究基因调控网络如何 心力衰竭期间控制特定心血管细胞类型的改变；以及3)检查扰动是如何 心力衰竭影响细胞的细胞型特异性顺式调控元件和基因调控网络 功能和基因表达。

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.