Publication Date

2011-12-08

Availability

Embargoed

Embargo Period

2013-12-07

Degree Type

Doctoral Essay

Degree Name

Doctor of Philosophy (PHD)

Department

Molecular and Cellular Pharmacology (Medicine)

Date of Defense

2011-11-16

First Committee Member

Nanette H. Bishopric

Second Committee Member

Grace Zhai

Third Committee Member

Sandra K. Lemmon

Fourth Committee Member

Zafar Nawaz

Fifth Committee Member

Peter Kang

Abstract

Myocardial transcriptional response to stress is critically dependent on availability of the histone acetyltransferase p300. p300 is a transcription coactivator which is rapidly induced by hemodynamic stress in the myocardium. This induction is both necessary and sufficient to drive myocardial hypertrophy in vivo. Although short-term elevation of p300 may be adaptive, sustained elevation of p300 increases the risk of heart failure. The mechanism of p300 induction during stress is unknown. The downstream effectors of p300 have been only incompletely elucidated. In this context, the role of microRNAs in regulating p300-driven cardiac hypertrophy can be of potential interest. MicroRNAs are short ~18-25 nucleotide non-coding RNAs that inhibit gene expression by inducing messenger RNA cleavage and blocking translation. Engagement of microRNAs by various transcription factors/coactivators is an important regulatory mechanism in angiogenesis and hypertrophy. However, the extent to which microRNAs act as downstream effectors and/or modulators of the p300-driven hypertrophic response is unknown. Preliminary data showed that miR20a, miR142 and miR374-5p were regulated during p300-driven cardiac hypertrophy and in acute ischemia. In addition, these microRNAs may target p300 as part of a feedback loop as p300 is one of the predicted targets. The goal of this project was to dissect the role of a subset of microRNAs including miR-20a, miR142 and miR374 during p300 regulated hypertophic growth in vitro and in vivo and to verify its targets. This study is important to delineate the role of microRNAs in the p300-dependent signaling network in the myocardium and may result in therapeutic benefit.

Keywords

miR20a- microRNA20A; miR142- microRNA142; miR374-microRNA374

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