: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.
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