Genome-wide Cardiac Transciption Patterns post-MI

University Of Wyoming, Laramie WY

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Abstract

DESCRIPTION (provided by applicant): Substantial alterations in gene expression must occur to produce the profound changes observed in surviving myocardium following ischemia leading to myocardial infarction (MI). Currently a genome-wide expression database for transcriptional changes in response to MI is not available. The production of such a database will aid in identification of the roles and potential interactions of many genes involved in the earliest signaling pathways post-MI. Thus the first aim is to establish an expression database for normal mouse left ventricle (LV) and from LV at selected time-points, starting from 15 min post-coronary artery ligation (ischemia) to 48 hrs post-MI. These time-points will thus encompass the earliest ischemic (minutes), inflammatory (minutes/hours/days), degradative and repair (hours/days) responses in the LV following coronary artery occlusion. Based on our preliminary findings for the first two proposed time-points, differences in the earliest patterns of gene expression within the LV are related to both duration of occlusion and proximity to the ischemic/infarcted zone. The second aim is to build testable model(s) of the signaling pathways in LV that are triggered by ischemia leading to infarction. In order to deeply mine the data, genes of known biochemical function will be analyzed separately from estimated sequence tags (ESTs). For known genes, both the primary literature and the implementation of computer-based natural language methods will be instrumental in their functional assignment to a particular biochemical or signaling pathway. For ESTs, a combination of standard clustering algorithms and domain/motif searches of protein databases will be used to generate patterns, classifications, and possible functional annotations. The long-range goal of this research is investigation of changes in the cardiac proteome in response to MI using knock-out and other transgenic mice to test specific hypotheses generated by analysis of the gene expression database. This grant will provide a research experience for two undergraduate students spanning two years, which will take advantage of the existing NSF and DOE EPSCoR infrastructure for undergraduate training at the University of Wyoming.