Transcriptional modules in human heart failure

描述(申请人提供)：在工业化国家，心力衰竭已成为成人住院的最常见原因。基础研究表明，病理性应激通过激活心脏转录因子(TF)促进心力衰竭。这些转录因子相互作用，并与辅助激活剂相互作用，形成“转录模块”(TMS)，改变心脏基因的表达，导致心肌细胞肥大和衰竭。鉴于TMS在心力衰竭发病机制中的关键作用，在过去的十年中，TMS一直是动物模型研究的对象。相比之下，TMS在人类心力衰竭中的作用在很大程度上仍未被探索，因为在人类受试者中研究TFS的方法有限。我们已经试行了计算方法，通过将来自微阵列实验的心脏基因表达数据与现成的基因组序列数据相结合，能够评估衰竭的人类心脏中的转铁蛋白功能。然而，这些并不足以解决潜在生物学的复杂性，需要更严格的方法。这一探索性/发展性研究提案的目的是使用精细的计算方法确定与人类心力衰竭相关的转录模块(TM)，并使用标准的体外技术对最有希望的TM进行实验验证。我们将开发新的综合方法来确定与人类心力衰竭相关的TM，并将它们应用于宾夕法尼亚队列研究，这是已出版文献中对人类心脏基因表达的最大研究。这些方法将全基因组表达数据与启动子序列、转铁蛋白结合基序和跨物种序列比对的数据结合在一起。我们最有希望的新发现的心力衰竭TM将通过使用体外心肌细胞报告基因分析进行实验验证。这项跨学科的建议将建立在临床研究员、计算生物学家、生物统计学家和分子生物学家之间现有的合作基础上。我们的研究将确定TMS与人类心力衰竭的发病机制直接相关。在这样做的过程中，我们将把动物模型方面的一项重要工作扩展到临床研究领域。我们确定的特定心力衰竭TMS将成为我们自己的团队和其他人未来研究的重点。这些研究可能最终导致针对肥厚转录机制的新药，肥厚是心力衰竭的一个中心特征，目前任何治疗方法都不直接针对它。最后，我们开发的计算方法应该广泛应用于研究其他人类疾病。在工业化世界，心力衰竭已经成为成人住院的最常见原因。过去十年进行的研究已经确定，心脏转录因子在心力衰竭的发病机制中发挥关键作用，但这些发现并未扩展到人类受试者。这项提议将开发和应用新的基因组方法来研究心脏转录因子在晚期心力衰竭患者中的作用。

DESCRIPTION (provided by applicant): Heart failure has become the most common reason for adult hospitalization in the industrialized world. Basic research has shown that pathologic stresses promote heart failure via activation of cardiac transcription factors (TFs). These TFs interact with each other and with co-activators to form "transcriptional modules" (TMs) that alter cardiac gene expression to cause myocyte hypertrophy and failure. In light of their critical role in heart failure pathogenesis, TMs have been the subject of intensive research in animal models over the past decade. By contrast, the role of TMs in human heart failure remains largely unexplored because of limited methods for studying TFs in human subjects. We have piloted computational approaches that enable assessment of TF function in the failing human heart by integrating cardiac gene expression data from microarray experiments with readily available genome sequence data. However, these do not sufficiently address the complexity of the underlying biology, and more rigorous methods are needed. The purpose of this exploratory/developmental research proposal is to determine transcriptional modules (TMs) associated with human heart failure using a refined computational approach and to experimentally validate the most promising TM using standard in vitro techniques. We will develop novel integrative approaches to determine TMs associated with human heart failure and apply them to the Penn Cohort, the largest study of human cardiac gene expression in the published literature. These approaches integrate whole genome expression data with data from promoter sequences, TF binding motifs, and cross-species sequence alignments. Our most promising newly identified heart failure TM will be validated experimentally using in vitro reporter gene assays in cardiac myocytes. This interdisciplinary proposal will build on existing collaboration between a clinical investigator, a computational biologist, a biostatistician, and a molecular biologist. Our research will determine TMs directly relevant to the pathogenesis of human heart failure. In doing so, we will extend an important body of work in animal models to the arena of clinical investigation. The specific heart failure TMs we identify will become the focus of future research performed by our own group and by others. These studies may ultimately lead to new drugs that target transcriptional mechanisms of hypertrophy, a central feature of heart failure that is not directly targeted by any current therapy. Lastly, the computational methods we develop should have broad application to study other human diseases. Heart failure has become the most common reason for adult hospitalization in the industrialized world. Research performed over the past decade has determined that cardiac transcription factors play a crucial role in the pathogenesis of heart failure, but these findings have not been extended to human subjects. This proposal will develop and apply novel genomic approaches to study the role of cardiac transcription factors in human subjects with advanced heart failure.