2012 |
Huang, Xupei |
R15Activity Code Description: Supports small-scale research projects at educational institutions that provide baccalaureate or advanced degrees for a significant number of the Nation’s research scientists but that have not been major recipients of NIH support. The goals of the program are to (1) support meritorious research, (2) expose students to research, and (3) strengthen the research environment of the institution. Awards provide limited Direct Costs, plus applicable F&A costs, for periods not to exceed 36 months. This activity code uses multi-year funding authority; however, OER approval is NOT needed prior to an IC using this activity code. |
Restrictive Cardiomyopathy Caused by Cardiac Troponin Mutations @ Florida Atlantic University
DESCRIPTION (provided by applicant): Cardiomyopathy is a common cardiac disorder and most inherited cases are caused by a single gene mutation. Restrictive cardiomyopathy (RCM), caused by cardiac troponin I (cTnI) mutations, is characterized by a restricted ventricle and diastolic dysfunction. The prognosis for patients with RCM is poor, as this condition often results in heart failure and sudden cardiac death. We have generated transgenic mice expressing a human RCM mutation on the C-terminus of cTnI, namely R192H (cTnI193His in mouse sequence) in the heart. The RCM cTnI transgenic mice show a phenotype similar to that observed in RCM patients, exhibiting biatrial enlargement, restricted ventricles and diastolic dysfunction. In this project, we propose to use these mouse models to define the cellular mechanisms of RCM by examining the effects of cTnI mutations on diastolic dysfunction and myocardial ischemia, which lead to heart failure and early death in RCM cTnI transgenic mice. Specifically, we will test the hypothesis that cTnI mutations enhance myofibril sensitivity to Ca2+ and causes impaired relaxation, which result in myocardial ischemia and, ultimately leading to heart failure and sudden cardiac death. Three specific aims have been developed to address the proposed hypothesis. Aim 1 will investigate how cTnI C-terminal mutations affect cardiac muscle contraction and relaxation in vitro and in vivo. Aim 2 will evaluate the effect of diastolic dysfunction on coronary blood supply and myocardial ischemia in RCM cTnI transgenic hearts. Aim 3 will study the mechanisms of heart failure in RCM cTnI transgenic mice in order to determine the cause of death in RCM. It is of great importance, both scientifically and clinically, to elucidate the cellular mechanisms underlying RCM caused by cTnI mutations in order to identify the cause of heart failure and death. Thus far, limited animal models for RCM are available to test the molecular mechanisms and the therapeutic outcomes in the intact chamber. Use of our mouse models and the data generated from the proposed studies, however, will have an important impact on the prevention and treatment of RCM and diastolic dysfunction. PUBLIC HEALTH RELEVANCE: Restrictive cardiomyopathy (RCM) is a cardiac disorder characterized by a stiffened heart and reduced blood filling to the heart chambers during diastole. Heart failure and early cardiac death are observed in patients with RCM, resulting from cardiac gene mutations. We generated a RCM mouse model by expressing the human cardiac troponin I mutation in the heart. The project proposes to use these RCM mouse models to investigate and ultimately define the mechanisms of the disease and the causes of death. Use of our mouse models and the data generated from the proposed studies will have an important impact on the prevention and treatment of RCM.
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