The goal of this K25 Mentored Quantitative Research Career Development Award application is for the candidate to develop expertise in the fields of cardiac-physiology and genetics in the context of a research plan investigating cardiomyopathy in a genetically engineered mouse model of muscular dystrophy. The training and research experience provided by this K25 award will enable the candidate to successfully transition from a background in Magnetic Resonance (MR) imaging physics to become an independent translational researcher performing research in pediatric cardiomyopathy and cardiovascular genetics. The proposed specific training goals include: expanding knowledge of molecular cardiac physiology and genetics, training in basic biological laboratory techniques, expanding knowledge of the etiology, diagnosis, and management of children with cardiomyopathy. The candidate's research plan investigates the pathogenesis of genetically inherited cardiomyopathy in d-sarcoglycan null, Scgd-/- mouse, a model of limb girdle muscular dystrophy under pharmacological intervention.
The specific aim 1 will determine the time course evolution of inflammation, fibrosis, lipid accumulation and cardiac dysfunction in Scgd-/- mice treated with TGF-? blocking agent in a longitudinal study using MRI, histopathology, biochemistry, protein analysis and cardiac catheterization.
The specific aim 2, will determine the relevance of microvascular perfusion deficit in the development of early regional cardiac dysfunction in Scgd-/- mice treated with vascular smooth muscle relaxant compared to untreated and normal control mice.
In aim 3, the relevance of increased left ventricular mechanical stress in the regional myocardial dysfunction and the development of fibrosis in aortic banded and un-operated Scgd-/- mice will be investigated in a longitudinal study. The experiments are designed to give hands on experience in basic biological laboratory techniques to the candidate. The proposed research plan will uncover the basic biology behind clinically applicable MR parameters in the framework of familial cardiomyopathy. Furthermore it will establish the mutual dependence of the structural and functional abnormalities of the cardiomyopathic heart in the early stages of the disease. With this training the Candidate will be in possession of unique set of tools that could translate what is known from animal studies to bedside and back. The Candidate will be mentored by a group of scientists (led by Dr. Jeffrey Towbin, Co-Director, Heart Institute, Cincinnati Children's Hospital) well established in the field molecular cardiovascular biology and pediatric cardiology. The training will be conducted jointly at the Heart Institute and at the University Of Cincinnati School Of Medicine. In addition to the interactive philosophy, both institutions have outstanding infrastructure to perform cutting edge science. Project Narrative: This study will identify early signs of cardiovascular disease that with treatment can positively impact the lives of children with genetically inherited muscular disorders. Furthermore, with training and research experience provided by this award the candidate will be able to design more effective experiments aimed at improving non-invasive imaging methods for evaluation of disease models.
This study will identify early signs of cardiovascular disease that with treatment can positively impact the lives of children with genetically inherited muscular disorders. Furthermore, with training and research experience provided by this award the candidate will be able to design more effective experiments aimed at improving non-invasive imaging methods for evaluation of disease models.
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