Xanthine Oxidase, Myocardial Genomics and Heart Failure

描述(由申请人提供)：心脏肥大是充血性心力衰竭的主要病理特征。先前的研究表明，氧化应激在体外诱导肥大基因的表达，这可能是人类心脏肥大的重要原因。申请人建议将他对临床研究的兴趣与最先进的基因组方法结合起来，以确定氧化应激如何促进人类心脏肥厚。根据初步数据，他将重点研究黄嘌呤氧化酶作为心肌氧化应激的来源。这一建议的中心论点是，心肌XO增加通过刺激肥大基因的转录而导致心力衰竭。在目标1中，申请者将使用Affymetrix微阵列来确定与移植失败的人类心肌肥大相关的基因。将使用多种分析方法，包括对预先选择的候选基因的基于假设的分析、探索性分析和基因表达模式的全球分析。在目标2中，申请者将证明在人类中心肌XO活动与这些肥大基因的表达相关。在目标3中，申请者将检验这样一个假设，即用别嘌醇抑制XO可以减少一系列心内膜心肌活检中肥大基因的表达，并防止扩张型心肌病患者心脏质量的增加。这些实验将确定XO在人类心肌中的转录靶点，从而阐明氧化应激在心力衰竭中的作用。更有甚者。它们是确定抑制XO是否是治疗心力衰竭的新策略的第一步。这项研究将在约翰·霍普金斯医疗机构进行，由心力衰竭氧化应激领域的专家约书亚·黑尔博士指导。基因组分析将与Hopgene PGAM在心肺疾病中的应用基因组学合作进行。申请人的跨学科培训、强大的导师指导、职业发展计划、支持性环境和新颖的研究计划将为他提供发展成为一名非常成功的独立临床研究员所需的经验和工具。

DESCRIPTION (provided by the applicant):Cardiac hypertrophy is a central pathologic feature of congestive heart failure. Prior investigations suggest that oxidative stress induces the expression of hypertrophy genes in vitro, and may be an important cause of cardiac hypertrophy in humans. The applicant proposes to merge his interest in clinical investigation with state-of-the-art genomic approaches to determine how oxidative stress promotes cardiac hypertrophy in humans. Based on preliminary data, he will focus on xanthine oxidase as a source of myocardial oxidative stress. The central thesis of this proposal is that increased myocardial XO contributes to heart failure by stimulating the transcription of hypertrophy genes. In Aim 1, the applicant will use Affymetrix microarrays to determine genes associated with hypertrophy in failing explanted human myocardium. Multiple analytic approaches will be used, including a hypothesis-based analysis of pre-selected candidate genes, exploratory analyses, and global analyses of patterns in gene expression. In Aim 2, the applicant will demonstrate that myocardial XO activity correlates with expression of these hypertrophy genes in humans. In Aim 3, the applicant will test the hypothesis that XO inhibition with allopurinol attenuates the expression of hypertrophy genes in serial endomyocardial biopsies, and prevents an increase in cardiac mass in patients with dilated cardiomyopathy. These experiments will determine the transcriptional targets of XO in human myocardium, thereby clarifying the role of oxidative stress in heart failure. Moreover. they are the first steps in determining whether XO inhibition is a novel treatment strategy for heart failure. This research will be performed at the Johns Hopkins Medical Institutions under the mentorship of Dr. Joshua Hare, an expert in the field of oxidative stress in heart failure. Genomic analyses will be performed in collaboration with the HopGene PGAmApplied Genomics in Cardiopulmonary Disease. The applicant's interdisciplinary training, strong mentorship, career development program, supportive environment, and novel research plan will give him the experience and tools he needs to develop into a highly successful, independent clinical investigator.