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dc.contributorNot Applicableen_US
dc.contributor.authorCANTY, JOHN M Principal Investigatoren_US
dc.date30-Apr-11en_US
dc.date2010en_US
dc.date.accessioned2011-04-18T21:03:48Zen_US
dc.date.accessioned2011-04-19T18:31:04Z
dc.date.available10-Jan-00en_US
dc.date.available2011-04-18T21:03:48Zen_US
dc.date.available2011-04-19T18:31:04Z
dc.date.issued2011-04-18T21:03:48Zen_US
dc.identifier7806611en_US
dc.identifier5R01HL061610-09en_US
dc.identifier61610en_US
dc.identifier.urihttp://hdl.handle.net/10477/1044
dc.descriptionangiogenesis;Apoptosis;Biological Assay;Cardiomyopathies;Cessation of life;Cicatrix;Coronary;Coupled;disability;Down-Regulation;enzyme activity;Enzymes;Family suidae;fetal;Fibrosis;Functional disorder;Funding;Gene Transfer;Heart failure;Hybrids;Hypertrophy;improved functioning;In Vitro;Ischemia;Left;Metabolic;Metabolism;Mitochondria;Mitochondrial Proteins;Modeling;Molecular;Muscle Cells;Myocardial;Myocardial dysfunction;Myocardium;novel;outcome forecast;Oxidative Stress;Pathway interactions;Patients;Physiological;prevent;protein expression;Proteomics;Recovery of Function;Research;Residual state;Respiration;Stunned Myocardium;Sudden Death;Tars;Testing;Therapeutic Intervention;Time;translational approach;translational study;en_US
dc.descriptionAmount: $ 496241en_US
dc.description.abstractDESCRIPTION (provided by applicant): Revascularization improves function and prognosis in patients with hibernating myocardium yet residual LV dysfunction is common. The mechanisms responsible for this are unclear but the dysfunction is disproportionate to the degree of myocardial scarring raising the possibility that it reflects residual myocyte cellular remodeling. During the previous funding period, we demonstrated that the progression from chronically stunned to hibernating myocardium is accompanied by apoptosis-induced myocyte loss, compensatory myocyte hypertrophy and metabolic adaptations that reduce regional energy utilization. While the proteomic profile is similar to the fetal and failing myocyte, the downregulation in regional function and metabolism limits oxidative stress to ultimately prevent further apoptosis. In the renewal application, we will determine whether the metabolic adaptations to ischemia which preserve myocyte viability ultimately limit functional recovery after revascularization. We propose a translational approach with parallel physiological, proteomic and mitochondrial functional studies in swine with viable chronically dysfunctional myocardium. Proteomic profiling will be used to identify candidate mitochondrial proteins in established swine models of viable dysfunctional myocardium that do not have significant fibrosis. These will be coupled with in vitro functional assays of mitochondrial respiration and candidate enzyme activity. Therapeutic interventions similar to those used in patients will allow us to identify plasticity in the molecular pathways responsible for adaptation and determine their importance in residual contractile dysfunciton. Aim 1 tests the hypothesis that regional alterations in mitochondrial protein expression and function distinguish hibernating from chronically stunned myocardium. Aim 2 tests the hypothesis that mitochondrial and contractile dysfunction persist after percutaneous coronary revascularization and determines the time course of functional recovery. Aim 3 tests the hypothesis that hybrid therapy with intracoronary AdvFGF-5 (which normalizes mitochondrial proteomic changes and improves function independently of angiogenesis) accelerates and enhances functional recovery after revascularization. Our long-term objective is to use this research to develop new strategies to reverse myocardial dysfunction in patients with ischemic cardiomyoapthy which will reduce death and disability from heart failure and sudden death.en_US
dc.titleMETABOLIC ADAPTATION AND FUNCTIONAL RECOVERY OF HIBERNATING MYOCARDIUMen_US
dc.typeNIH Grant Awarden_US


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