Dynamics of Cardiac Nuclei in Heart Disease

项目总结/摘要 心力衰竭是一种进行性综合征，需要新的机制见解。 心脏 已知肥大涉及改变肌细胞功能的胎儿基因程序的激活。 最近 来自非心脏领域的研究已经对核小体定位和染色质进行了全基因组分析， 技术上可行。 我们推断，必须存在精心策划的染色质重塑事件， 促进心脏基因的表达，并提出像心力衰竭这样的疾病与染色质紊乱有关， 在基因组的尺度上。 这项工作的短期目标是了解细胞核中蛋白质的整体， 这些蛋白质在心脏肥大和核小体定位的改变，发生与 疾病这些问题将在临床相关的压力超负荷诱导的小鼠模型中进行。 心脏肥大和衰竭。这个项目的长期目标是整合这些概念， 细胞核蛋白质组成的变化如何影响核小体，从而改变其组成， 翻译后修饰导致整个基因组的染色质结构改变。 我们的统一假设是肥大刺激调动了一个蛋白质网络，改变了心脏- 在正常发育过程中发生的特异性染色质包装，使肌细胞恢复为更胎儿的状态， 导致心脏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了我们对心力衰竭的理解。主要优势 这一应用的创新之处在于，我们提供了一个新的假设，得到了强有力的初步数据的支持， 解释了心力衰竭时心脏表型是如何被重新编程的。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如何 心脏蛋白质组影响基因组以调节染色质结构，从而调节心脏表型。 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疾病中的作用。 表型。 这些知识将为基因组如何重新编程提供一个机械基础， 并帮助建立新的治疗模式。

PROJECT SUMMARY/ABSTRACT 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.