ROLE OF EPIDERMAL GROWTH FACTOR RECEPTOR ON CARDIAC FUNCTION Public Deposited

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Last Modified
  • March 19, 2019
Creator
  • Xie, Yuying
    • Affiliation: School of Medicine, Curriculum in Genetics and Molecular Biology
Abstract
  • The epidermal growth factor receptor (EGFR/ERBB1) was the first discovered member of the ERBB family of tyrosine kinas receptors that includes ERBB2, ERBB3 and ERBB4. After binding by EGF-related ligands, EGFR is activated to induce homodimerization or heterodimerization with other ERBB receptors, resulting in tyrosine kinase activity. Subsequently, autophosphorylation or transphosphorylation of tyrosine residues in the C-terminal tail of the receptor allows the binding of adaptor proteins to trigger intracellular signaling cascades that can lead to proliferation, survival, and anti-apoptosis. As EGFR is expressed in the majority of developing and adult tissues including heart, dysfunction of EGFR activity can cause severe damage in different tissues and even initiate cancers. Several anti-EGFR drugs are already available in the clinic for late stage cancer patients with activated EGFR activity. However, in cancer therapy using anti-ERBB2 drugs, severe cardiotoxicity among patients has been reported, emphasizing the importance of ERBB signaling in cardiac homeostasis. Also with the increases in life expectancy of patients, some types of cancers tend to be treated as a chronic disease. Therefore it is importance to understanding possible cardiac toxicity under chronic suppression of EGFR pathway. We propose the use of conditional knockout mice lacking EGFR activity in cardiomyocytes to understand the role of EGFR signaling in normal cardiac function. We demonstrated that chronic repression of EGFR pathway would cause severe cardiac dysfunction with chamber dilations, left ventricular wall thinning and depressed cardiac function. Left ventricular hypertrophy (LVH) is associated with many cardiovascular diseases and is a risk factor for cardiac related morbidity and mortality. Mice homozygous with EGFR hypomorphic mutation display various background dependent phenotypes including left ventricle hypertrophy. Using two different strains, we mapped a quantitative trait locus (QTL) associated with cardiac hypertrophy. These studies should be useful in understanding the development of LVH and in predicting patients susceptible to cardiatoxicity induced by chronic use of anti-EGFR drugs.
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  • In Copyright
Advisor
  • Manuel Pardo-Pardo-Manuel de Villena, Fernando
  • Sun, Wei
  • Threadgill, David W.
  • Wang, Wei
  • Wiltshire, Timothy
Degree
  • Doctor of Philosophy
Degree granting institution
  • University of North Carolina at Chapel Hill Graduate School
Graduation year
  • 2015
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  • Chapel Hill, NC
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