Date of Award

Spring 1-1-2015

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Biology

First Advisor

Robert Garcea

Second Advisor

Leslie Leinwand

Third Advisor

Kevin Jones

Fourth Advisor

Timothy McKinsey

Fifth Advisor

Min Han

Abstract

The mammalian heart is a remarkably adaptable organ. In particular, the contractile cells of the heart, the cardiac myocytes can respond to dramatic changes in metabolic and functional demand. Both clinical data and murine genetic studies suggest fundamental differences in male and female cardiac biology, including at the cellular level of the myocyte. In this thesis, I address the clinical question of why cardiovascular disease differs in males and females at the cardiac myocyte level. Specifically, I elucidate the importance and mechanism of estrogen signaling in male and female cardiac myocytes. Upon identifying Estrogen Receptor-α (ERα) as the predominant estrogen receptor in cardiac myocytes, I generated a cardiac myocyte-specific ERα knockout mouse using an established cardiac myocyte-specific Cre recombinase driver. I characterized the molecular and functional consequences of deleting ERα in cardiac myocytes and in doing so uncovered a novel, cardiotoxic effect of Cre recombinase expression in cardiac myocytes. I therefore performed a molecular, functional, and bioinformatic analysis of the most commonly used cardiac myocyte-specific Cre expression model. In parallel with my in vivo experiments, I assessed subcellular localization, signaling activation, and transcriptional competency of full-length ERα and two alternate spliceforms in isolated cardiac myocytes to address the cellular mechanism of ERα activity in cardiac myocytes. Altogether, this thesis sheds light on the sexually dimorphic nature of cardiac myocyte biology and the influence of such on overall cardiovascular function.

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