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Modulation of mitogenic signaling and growth by sympathetic adrenergic regulation

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Title: Modulation of mitogenic signaling and growth by sympathetic adrenergic regulation
Author(s): Cervantes, David
Advisor(s): Xiang, Yang
Contributor(s): Nardulli, Ann; Chen, Jie; Raetzman, Lori
Department / Program: Molecular & Integrative Physl
Discipline: Molecular & Integrative Physi
Degree Granting Institution: University of Illinois at Urbana-Champaign
Degree: Ph.D.
Genre: Doctoral
Subject(s): adrenergic receptor insulin receptor extracellular signal-regulated kinase (ERK) heart arrestin
Abstract: Heart disease and diabetes mellitus are growing epidemics, consistently ranking within the top ten causes of death in the United States. Both diseases are associated with cardiac remodeling, including cellular growth and fibrosis. Central to the progression of heart disease and diabetes are the adrenergic receptors (ARs) and insulin receptors (IR), respectively. Classically considered to elicit separate, and even opposing, cellular processes, increasing evidence suggests that ARs are capable of signaling cross-talk with other G-protein coupled receptors (GPCRs) as well as other receptor families, including receptor tyrosine kinases (RTKs). While the ARs have been implicated at numerous stages of heart failure, the adrenergic signaling mechanisms underlying this remodeling remain unknown. Further, studies investigating signaling cross-talk among different adrenergic receptors as well as between adrenergic receptors and other signaling pathways in myocardium remain in their infancy. In addition, few studies have implied functional interactions between IRs and βARs in cardiac tissues. Understanding how cells integrate information from a variety of chemically diverse signals into complex, orchestrated responses such as cell proliferation, differentiation and apoptosis is an overarching goal of cell biology. Thus, an understanding of the mechanisms and physiologic consequences of adrenergic receptor cross-talk within the heart is essential to develop novel treatments designed to prevent the cardiac remodeling observed in heart disease and diabetes. In concordance, the goals of this thesis research are two-fold. First, we aim to define mechanisms of AR cross-talk in cardiac cells. Secondly, we aim to determine the importance of these mechanisms in cardiac remodeling in response to pathological conditions. To begin to address the goals presented we first examined cross-talk within GPCRs. We elucidated a general mechanism in which non-traditional GPCR signaling is capable of regulating mitogen-activated protein kinase (MAPK) signaling originating from another GPCR. Interestingly, this cross-talk impaired GPCR-induced cellular proliferation. Next, we characterized a novel signaling mechanism in which type II RTK activation at high concentrations of mitogen can recruit non-traditional GPCR signaling components to fine-tune activation of MAPK signaling for cell proliferation. In sum, this work presents a significant expansion of our understanding of GPCR signaling cross-talk and its role in altering growth signaling originating from another receptor. Further, due to the complexities of hormonal signaling in vivo, this work highlights the need to further pursue a more in-depth understanding of how concomitant activation of one signaling pathway can alter the signaling and physiologic outcome of another receptor’s signaling.
Issue Date: 2012-02-06
Genre: thesis
URI: http://hdl.handle.net/2142/29837
Rights Information: Copyright 2011 Dave Cervantes
Date Available in IDEALS: 2012-02-06
Date Deposited: 2011-12
 

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