Semester

Fall

Date of Graduation

2020

Document Type

Dissertation

Degree Type

PhD

College

School of Medicine

Department

Physiology, Pharmacology & Neuroscience

Committee Chair

Stanley Hileman

Committee Member

Han-Gang Yu

Committee Member

Timothy Nurkiewicz

Committee Member

Karen Martin

Committee Member

Kathleen Brundage

Abstract

Heart failure is a lifelong disability that for over half of those affected leads to mortality within five years after initial diagnosis. Left ventricular hypertrophy (LVH) is one of the most reliable independent predictors of heart failure. Pathological LVH is irreversible, but early diagnosis is often missed due to its asymptomatic nature. Obese Zucker rats (OZR), which develop obesity due to dysfunctional leptin signaling, naturally exhibit a LVH that mimics the obese human condition. Animal models are necessary because human donor tissue is scarce. The central hypothesis is that genes and proteins that are differentially expressed during development of LVH, relative to sex and obesity status, will serve as clinical biomarkers or therapeutic targets for detection and prevention of heart failure. No previous studies have addressed LVH on an exome-wide basis. In the present research, I address these knowledge gaps with transcriptome analysis of rat and human left ventricles in a sex- and obesity-specific manner. Specific genes (NPPA, NPPB, HBB, MYL7, PDK4) known to be involved in cardiac development and function were then validated proteomically to form a LVH gene signature that may be useful for future diagnosis or represent targets for intervention. This work defines novel LVH transcriptomes in humans and OZR and these datasets allow for confirmation of whether an individual gene or geneset is translationally-relevant for further investigation in LVH. Future work should address transcriptomic and proteomic changes throughout LVH development and whether intervention targeting specific gene products can ameliorate onset of LVH.

Embargo Reason

Publication Pending

Available for download on Monday, August 16, 2021

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