Dynamics of Cardiac Nuclei in Heart Disease

心脏病中心脏细胞核的动态

• 批准号: 8024317
• 负责人: Thomas M. Vondriska
• 金额: $ 38.5万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-01-01 至 2015-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8024317
• 关键词: Acetylation; Adult; Affect; Behavior; Bioinformatics; Cardiac; Cardiac Myocytes; Cell Nucleus; Cells; Chromatin; Chromatin Structure; DNA; DNA Sequence; DNA Sequence Rearrangement; Data; Development; Digestion; Disease; Educational process of instructing; Enzymes; Eukaryota; Evaluation; Event; Failure; Gene Expression; Gene Expression Regulation; Gene Proteins; Genes; Genetic Transcription; Genome; Genomics; Goals; Heart; Heart Diseases; Heart Hypertrophy; Heart failure; Higher Order Chromatin Structure; Histone H2A; Histones; Hypertrophy; Investigation; Knowledge; Life; Location; Maps; Measures; Methods; Methylation; Micrococcal Nuclease; Modification; Molecular; Muscle Cells; Nuclear; Nuclear Proteins; Nucleosomes; Pattern; Phase; Phenotype; Positioning Attribute; Post-Translational Protein Processing; Protein Binding; Protein Isoforms; Proteins; Proteome; Proteomics; Public Health; Regulation; Role; SPT6 Protein; Staging; Stimulus; Structure; Syndrome; System; T-Lymphocyte; Technology; Testing; Work; base; cell type; chromatin immunoprecipitation; chromatin remodeling; clinically relevant; fetal; fetal programming; genome wide association study; genome-wide; genome-wide analysis; innovation; insight; mouse model; mutant; next generation; novel; pressure; prevent; primitive cell; programs; protein complex; research study; response; transcription factor

DESCRIPTION (provided by applicant): Heart failure is a progressive syndrome for which novel mechanistic insights are needed. Cardiac hypertrophy is known to involve activation of a fetal gene program that alters myocyte function. Recent studies from the non-cardiac field have made genome-wide analysis of nucleosome positioning and chromatin structure technically feasible. We reason that well-orchestrated chromatin remodeling events must exist to facilitate cardiac gene expression and propose that diseases like heart failure involve deranged chromatin structure at the genomic scale. The short term goal of this work is to understand the totality of proteins in the nucleus, the changes in these proteins during cardiac hypertrophy and the alterations in nucleosome positioning that occur with disease. These questions will be pursued in a clinically-relevant mouse model of pressure overload-induced cardiac hypertrophy and failure. The long term goal of this project is to integrate these concepts to understand how the changing protein makeup of the nucleus impinges on nucleosomes to alter their composition and post-translational modification leading to modified chromatin structure across the genome. Our unifying hypothesis is that hypertrophic stimuli mobilize a protein network that alters the cardiac- specific chromatin packaging that occurs during normal development, reverting the myocyte to a more fetal- like state and causing heart failure. This application leverages state-of-the-art proteomic and next generation DNA sequencing technology to conceptually advance our understanding of heart failure. The major strength of this application is innovation-we provide a novel hypothesis, supported by strong preliminary data, explaining how cardiac phenotype is reprogrammed during heart failure. Our approach will reveal discrete molecular mechanisms, but moreover, it has the potential to provide paradigm changing insights into how the cardiac proteome impinges on the genome to regulate chromatin structure and thereby cardiac phenotype. The insights gained from this work have direct relevance to the public health problem of heart failure. These studies will map the nuclear proteome and discern the role of nucleosome positioning in cardiac phenotype. This knowledge will provide a mechanistic basis for how the genome is reprogrammed with disease and help establish new paradigms for therapy. PUBLIC HEALTH RELEVANCE: Heart failure is a deadly syndrome for which novel mechanistic insights are desperately needed. We hypothesize that changes in proteins interacting with DNA during disease fundamentally alter the higher order structure of DNA by affecting positioning and modifications of chromatin structural proteins. These studies will provide the first insights into dynamics of chromatin structure in the heart and have the potential to establish a new paradigm for how the genome affects the behavior of the heart during disease.

描述（由申请人提供）：心力衰竭是一种进行性综合征，需要新的机制见解。 已知心脏肥大涉及改变肌细胞功能的胎儿基因程序的激活。 非心脏领域的最新研究使核小体定位和染色质结构的全基因组分析在技术上可行。 我们的理由是，精心策划的染色质重塑事件必须存在，以促进心脏基因的表达，并提出心脏衰竭等疾病涉及在基因组规模的染色质结构紊乱。 这项工作的短期目标是了解细胞核中蛋白质的总体，这些蛋白质在心脏肥大期间的变化以及疾病发生时核小体定位的改变。这些问题将在压力超负荷诱导的心脏肥大和衰竭的临床相关小鼠模型中进行。该项目的长期目标是整合这些概念，以了解细胞核蛋白质组成的变化如何影响核小体，以改变其组成和翻译后修饰，从而导致整个基因组的染色质结构发生改变。 我们的统一假设是，肥大刺激动员了一个蛋白质网络，改变了正常发育过程中发生的心脏特异性染色质包装，使肌细胞恢复到更像胎儿的状态，并导致心力衰竭。该应用程序利用最先进的蛋白质组学和下一代DNA测序技术，在概念上推进我们对心力衰竭的理解。这项应用的主要优势在于创新-我们提供了一个新的假设，并得到了强有力的初步数据的支持，解释了心力衰竭期间心脏表型是如何重新编程的。我们的方法将揭示离散的分子机制，但此外，它有可能提供范式改变的见解，心脏蛋白质组如何影响基因组，以调节染色质结构，从而心脏表型。 从这项工作中获得的见解与心力衰竭的公共卫生问题直接相关。 这些研究将绘制核蛋白质组图，并识别核小体定位在心脏表型中的作用。 这些知识将为基因组如何随着疾病重新编程提供机制基础，并帮助建立新的治疗模式。 公共卫生相关性：心力衰竭是一种致命的综合征，迫切需要新的机制见解。 我们假设，在疾病过程中与DNA相互作用的蛋白质的变化从根本上改变了DNA的高阶结构，通过影响染色质结构蛋白的定位和修饰。 这些研究将首次深入了解心脏染色质结构的动态，并有可能为基因组如何影响疾病期间心脏的行为建立新的范式。