Semester

Summer

Date of Graduation

2011

Document Type

Dissertation

Degree Type

PhD

College

School of Medicine

Department

Microbiology, Immunology, and Cell Biology

Committee Chair

Han-Gang Yu

Abstract

Cardiac sudden death (CSD) is the leading cause of death in the United States. Although the causes of CSD are not understood completely, cardiac arrhythmias have been indicated as the major contribution to CSD. The main purpose of this thesis is to investigate the mechanisms underlying cardiac arrhythmias, therefore providing scientific basis for clinical applications in the future to lower the rate of CSD.;My thesis contains four chapters. Chapter 1 aims to examine a novel role of tyrosine phosphorylation in the arrhythmogenesis. To achieve this goal, a rat arrhythmia model was established without structural remodeling, and the Src tyrosine kinase and protein tyrosine phosphatase were evaluated in the induction of cardiac arrhythmias by using electrocardiography (ECG) technique (two manuscripts are in preparation).;In chapter 2, we elucidate the mechanism tyrosine phosphorylation used to modulate the cardiac pacemaker channels that directly contribute to the regulation of heart rate and their potential new role in cardiac arrhythmias (J Biol Chem 284: 30433-30440, 2009).;In chapter 3, we explore a novel role of Hyperpolarization-activated, cyclic nucleotide-gated (HCN) channels serving as a regulatory protein to regulate the Ca2+ influx via inactivation of L-type calcium channel (LTCC) (Am J Physiol Cell Physiol 298(5): C1029-37, 2010).;In chapter 4, the results that have not been published are summarized. These results represented my efforts to explore previously unrecognized mechanisms that underlie the genesis and development of cardiac arrhythmias that predispose the heart to CSD, claiming more than 300,000 lives each year in the US.;Collectively, our results indicate that tyrosine phosphorylation plays a critical role in the regulation of cardiac rhythm, possibly via modulation the activities of HCN pacemaker channels. Furthermore, we also found that HCN channels can limit the Ca2+ influx via induction of fast inactivation of LTCC. These results not only help us to better understand the mechanisms of cardiac arrhythmias, but can also be applied to the future drug development for the prevention of CSD caused by cardiac arrhythmias.

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