Dynamics of Cardiac Nuclei in Heart Disease

项目摘要/摘要 心力衰竭是一种进行性综合征，需要新的机制洞察力。心脏 众所周知，肥大与激活胎儿基因程序有关，该程序改变了心肌细胞的功能。近期 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 结构在技术上是可行的。我们推断，精心策划的染色质重塑事件必须存在于 促进心脏基因表达，并提出心力衰竭等疾病与染色质错乱有关 基因组水平的结构。 这项工作的短期目标是了解细胞核中蛋白质的总量，核内蛋白质的变化 心肌肥厚过程中的这些蛋白质以及核小体定位的改变 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探索 心肌肥大和衰竭。该项目的长期目标是将这些概念整合在一起，以理解 核蛋白组成的变化如何影响核小体改变其组成和 翻译后修饰导致整个基因组染色质结构的改变。 我们的统一假设是，肥大刺激动员了一个蛋白质网络，改变了心脏- 在正常发育过程中发生的特殊染色质包装，使肌细胞恢复到更胎儿的状态- 就像状态一样，并导致心力衰竭。这一应用利用了最先进的蛋白质组学和下一代 DNA测序技术从概念上促进了我们对心力衰竭的理解。主要优势 这一应用的关键是创新--我们提供了一个新的假设，并得到了强大的初步数据的支持， 解释心力衰竭时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，但更重要的是，它有可能提供改变范式的洞察力 心脏蛋白质组作用于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组图，并识别核小体定位在心脏疾病中的作用。 表型。这一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.