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"SYSTEMS ANALYSIS OF mRNA EXPRESSION
IN CARDIAC DEVELOPMENT AND DISEASE"

by
Ji Yeon Park
Cell Biology and Molecular Medicine
M.S. 1998, Ewha Womans University



Thesis Advisor: Bin Tian, Ph.D.
Associate Professor
Department of Biochemistry and Molecular Biology

Wednesday, May 4, 2011
MSB G-609, 1:00 P.M.


Abstract

The research presented in this thesis comprises bioinformatic analyses of gene expression in cardiac development, hypertrophy, and ischemic preconditioning (IPC).

Cardiac hypertrophy is enlargement of the heart in response to physiological or pathological stimuli. Previous studies have shown that the expression pattern of a group of genes in pathological hypertrophy resembles that at the embryonic stage of heart development. Here, using a genome-wide approach, we systematically defined genes, pathways, and regulatory modules involving transcription factors and microRNAs that are robustly regulated in rodent cardiac hypertrophy models, and compared them with those regulated at different stages of embryonic and postnatal development. In addition, exon-level analysis revealed widespread mRNA isoform changes during cardiac hypertrophy resulting from alternative usage of terminal or internal exons, some of which were also developmentally regulated and may be attributable to decreased expression of Fox-1 protein in cardiac hypertrophy. Moreover, we found 3’UTRs of mRNAs were generally shortened through alternative cleavage and polyadenylation in hypertrophy. Taken together, our results comprehensively delineated gene and mRNA isoform regulations in cardiac hypertrophy and revealed their relations to those in development, and suggested that modulation of mRNA isoform expression plays an important role in heart remodeling under pressure overload.

IPC induces cardioprotection against lethal myocardial ischemia. We employed microarray analyses to examine three swine IPC models, including second-window of preconditioning (SWOP), repetitive coronary occlusion (RCO), and repetitive coronary stenosis (RCS). All three models reduced infarct size by 60-85%. We found there was high similarity in gene response between the RCO and RCS models, whereas SWOP was qualitatively different. Both RCO and RCS, but not SWOP, resulted in downregulation of genes involved in oxidative metabolism and upregulation of genes involved in immune response. Therefore, the regulated genes mediating IPC with repetitive ischemia differ radically from SWOP, showing that a repetitive pattern of ischemia, rather than the difference between no-flow vs. low-flow ischemia, dictates the genomic response of the heart. These findings illustrate new cardioprotective mechanisms developed by repetitive IPC, which are potentially more relevant to patients with chronic ischemic heart disease, who are subject to repetitive episodes of ischemia.


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