Cardiac Lineage-Specific Molecular Mechanisms of Heart Failure

心力衰竭的心脏谱系特异性分子机制

• 批准号: 10852685
• 负责人: Neil C Chi
• 金额: $ 63.63万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 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/10852685
• 关键词: ATAC-seq; Address; Administrative Supplement; Adult; Affect; Applications Grants; Cardiac; Cardiac Myocytes; Cardiac conduction system; Cardiovascular Diseases; Cardiovascular system; Cell Lineage; Cell Maintenance; Cell physiology; Cells; Chromatin; Collaborations; Data; Defect; Disease; EFRAC; Endothelium; Enhancers; Fibroblasts; Fluorescent in Situ Hybridization; Gene Expression; Gene Expression Profile; Gene Expression Regulation; Genetic; Goals; Grant; Heart; Heart Atrium; Heart Diseases; Heart Valve Diseases; Heart Valves; Heart failure; Human; Image; Joints; Maps; Mediating; Mitral Valve; Molecular; Morbidity - disease rate; National Heart, Lung, and Blood Institute; Nuclear; Outcome; Parents; Pathologic; Patients; Performance; Phenotype; Population; Regulator Genes; Regulatory Element; Research; Smooth Muscle Myocytes; Structure; Technology; cell type; cohort; epigenomics; gene network; gene regulatory network; genetic variant; genomic profiles; heart function; in vivo; interest; mortality; multiple omics; parent grant; programs; promoter; response; single cell sequencing; transcriptome sequencing

Project Summary The heart consists of a multitude of diverse cardiac cell types that form cardiac structures critical for maintaining heart function. These cell populations include not only cardiomyocytes, cardiac fibroblasts, epicardial cells, endothelial/endocardial cells and smooth muscle cells, but also more specialized cell types comprising the cardiac valves, cardiac conduction system, etc. 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 (HF), which is a major leading cause of morbidity and mortality worldwide. However, what are the specific cell lineages affected during HF and how do gene regulatory networks (GRNs) control genetic programs that direct their pathologic outcomes are key biomedical questions that we seek to address in our parent R01HL156576 grant. Toward this end, this grant proposal has mainly focused on analyzing the cardiac chambers (i.e., ventricles and atria) but not cardiac valves, which can be defective and diseased in HF and in some cases can be the cause of HF. Thus, to expand our efforts and examine all cell-types participating in failing and non-failing human hearts in vivo including the cardiac valves, we propose to implement joint single cell/nuclear (sc/sn) RNA-seq and ATAC-seq technologies (i.e., single cell multi-omics) on not only the cardiac chambers as originally proposed in our parent grant but also the cardiac valves, particularly mitral valve, in response to the Notice of Special Interest (NOSI): Administrative Supplements to Encourage Research in Valvular Heart Disease (CAROL Act, NOT-HL-23-078). In addition to identifying distinct CV cell-types and their related transcriptional profiles and chromatin landscape, we further seek to elucidate the interactions between cell-type specific cis-regulatory elements (CREs), which mediate the GRNs that control how CREs direct gene expression of these cell types in the cardiac (mitral) valves of failing and non-failing hearts. Furthermore, because the structural form of the cardiac valve is critical for regulating its function, we propose to further investigate the spatial organization of identified cell types in the cardiac valves, particularly mitral valves, of human hearts with and without heart failure and cardiac valve defects/disease. Thus, the overall goal of this supplement to our original parent grant is to generate single-cell multi-omics and spatial imaging data of cardiac valves, particularly mitral valves, from a large, well-phenotyped cohort of patients with and without heart failure and mitral valve defects/disease. We will then create comprehensive maps of cell-type specific gene regulation including integrated genomic profiles and spatial localization of all cells and cis-regulatory programs in each cell type.

项目摘要 心脏由多种形成心脏结构的多种心脏细胞类型组成 保持心脏功能。这些细胞群不仅包括心肌细胞，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，但也更专业的细胞类型 包括心脏瓣膜，心脏传导系统等 类型对于最佳心脏表现至关重要，破坏特定细胞谱系的功能可能会导致 包括心力衰竭（HF）在内的独特心脏病，这是发病率和死亡率的主要主要原因 全世界。但是，在HF期间受影响的特定细胞谱系和基因调节如何 网络（GRNS）控制指导其病理结果的遗传程序是关键的生物医学问题 我们寻求在父母R01HL156576赠款中解决。为此，该赠款提议主要是 专注于分析心脏室（即心室和心房），而不是心脏瓣膜 在HF中，在某些情况下可能是HF的原因。因此，扩大我们的努力和 检查所有参与体内失败和未击败人心心脏的细胞类型，包括心脏瓣膜， 我们建议实施联合单细胞/核（SC/SN）RNA-seq和ATAC-Seq Technologies（即单细胞 多词）不仅在我们的父母赠款中最初提出的心脏室，还包括心脏 阀门，特别是二尖瓣，以应对特殊关注通知（NOSI）：行政 补充剂以鼓励瓣膜心脏病研究（Carol Act，NOT-HL-23-078）。此外 确定不同的CV细胞类型及其相关的转录曲线和染色质景观，我们进一步 寻求阐明细胞类型特异性顺式调节元件（CRE）之间的相互作用，该元件介导了 控制这些细胞类型的基因表达如何在失败的心脏（二尖瓣）瓣中引导基因表达的GRN 和非失败的心。此外，因为心脏瓣膜的结构形式对于调节其调节至关重要 功能，我们建议进一步研究心脏瓣膜中已鉴定的细胞类型的空间组织， 特别是二尖瓣，有或没有心力衰竭的人类心脏和心脏瓣膜缺陷/疾病。 因此，这项补充给我们原始父母赠款的总体目标是生成单细胞多摩斯和 来自大型，良好的队列的心脏瓣膜，尤其是二尖瓣的空间成像数据 患有或没有心力衰竭和二尖瓣缺陷/疾病的患者。然后，我们将创建全面 细胞类型特异性基因调节的地图，包括整合基因组谱和所有空间定位 每种细胞类型中的细胞和顺式调节程序。