This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Cardiac proteins such as troponin T, titin and serum response factor are reported to have alternative splicing isoform shifts in cardiac hypertrophy and heart failure. Most of these isoform shifts are from longer to shorter resulting from exon skipping and are associated with distinct pathophysiological phenotypes in the hypertrophying and failing heart. However, little is known about the mechanisms of the alternative splicing changes stimulated by mechanical stress in hypertrophic and failing failure. Our significant finding that several splicing factors upregulate or downregulate their expression levels in heart failure offers a novel insight into the factors that may be involved in the splicing shifts of important cardiac contactile proteins that contribute to the pathology of heart failure. I propose to characterize the molecular mechanism by which different splicing factors mediate the splicing pattern shifts of cardiac proteins in the failing heart. My central hypothesis is that the expression level, state of phosphorylation, and subcellular localization of the splicing regulatory proteins that regulate exon skipping and isoform shift of important cardiac proteins change in heart failure, contributing to the distinct pathophysiological phenotypes associated with heart failure. The following specific aims are proposed to test this hypothesis:
Specific Aim 1 : Characterize the expression patterns, relocalization, and phosphorylation state of the splicing regulatory proteins in the failing heart caused by the pressure overload.
Specific Aim 2 : Examine the splicing isoform changes in cardiac proteins in the failing heart and determine whether the changes of the splicing regulatory proteins are both necessary and sufficient for the splicing shift of the cardiac proteins. Results generated in this study will reveal new mechanisms behind the splicing isoform shift of cardiac proteins contributing to contactile dysfunction and heart failure. Knowledge of these mechanisms will ultimately lead to new therapeutic strategies for heart failure.
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