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C-terminal Peptide of Cardiac Troponin I for the Treatment of Diastolic Hear Failure

心肌肌钙蛋白 I C 端肽治疗舒张性心力衰竭

基本信息

批准号：
10658193
负责人：
Jian-Ping Jin
金额：
$ 39.98万
依托单位：
UNIVERSITY OF ILLINOIS AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-05-01 至 2027-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10658193
关键词：
Actomyosin Adenosinetriphosphatase Adrenergic Agents Adult Aging Amino Acids Animals Binding Binding Sites Biochemical C-terminal Calcium-Sensing Receptors Cardiac Cardiac Muscle Contraction Cardiac Myocytes Cardiac Output Cardiovascular system Chemicals Chronic Clinical Clinical Treatment Complex Congestive Heart Failure Cyclic AMP-Dependent Protein Kinases Data Development Diastolic heart failure Disease EFRAC Embryonic Heart Failure Functional disorder Future Genes Genetic Goals Hearing Heart Heart failure Homing Human Impairment Kinetics Length Mediating Medical Methodology Microfilaments Modeling Molecular Conformation Molecular Structure Morbidity - disease rate Mus Muscle Muscle function Muscle relaxation phase Mutation Myocardial Myocardial dysfunction Myocardium Myofibrils Myosin ATPase N-terminal Peptides Pharmaceutical Preparations Phosphorylation Physiological Physiology Play Protein Isoforms Protein Subunits Pump Reagent Regulation Relaxation Research Research Project Grants Rest Role Sarcomeres Site Skeletal Muscle Skin Stress Stroke Volume Structure Structure-Activity Relationship Sturnus vulgaris Therapeutic Therapeutic Effect Thin Filament Thinness Transgenic Mice Translating Treatment Efficacy Tropomyosin Troponin Troponin C Troponin I Troponin T Ventricular Remodeling Vertebrates data modeling desensitization dimer effective therapy heart function hemodynamics improved in vivo in vivo evaluation innovation molecular modeling mortality mouse model novel novel therapeutics peptide drug preservation programs protein structure function reconstitution response side effect targeted treatment therapeutic target transgene expression translational potential

项目摘要

Project Title: C-terminal Peptide of Cardiac Troponin I for the Treatment of Diastolic Heart Failure Project Summary Myocardial contractility is essential for cardiac function. Troponin-mediated thin myofilament regulation controls cardiac muscle contraction and relaxation. The troponin complex consists of three protein subunits: the calcium receptor troponin C (TnC), the inhibitory subunit troponin I (TnI), and the tropomyosin-binding subunit troponin T (TnT). Cardiac TnI plays a pivotal role in myofilament activation and deactivation, determining the kinetics of cardiac muscle contraction and relaxation, and pumping efficiency of the heart. Our research project focuses on a novel therapeutic peptide derived from the conserved C-terminal end mobile domain of cardiac TnI (cTnI-C27) for its effect on enhancing myocardial relaxation and the underlying mechanisms. Biochemical, genetic and physiological approaches and mouse models of diastolic cardiac dysfunction are employed to study cTnI-C27 peptide to understand its selective enhancement of diastolic function of the heart. The ultimate goal is to develop a targeted treatment for diastolic heart failure (HFpEF) that presently lacks an effective treatment. Three Specific Aims are proposed in the research plan: Aim 1 is to characterize the mechanism for exogenous cTnI-C27 peptide to modulate myofilament function as an activated state-specific myofilament Ca2+- desensitizer. We shall determine the binding site of cTnI-C27 peptide on tropomyosin in thin filament and characterize its effect on contractile kinetics and endogenous troponin regulation of myofibril actomyosin ATPase in reconstituted myofilaments and skinned cardiac muscle. The results will determine how exogenous cTnI-C27 peptide modulates cardiac muscle contractility, especially the enhanceing of Frank-Starling response without increasing sarcomere length. Aim 2 is to study the delivery of cTnI-C27 peptide into cardiomyocytes for functional effect. Heart-homing fusion peptide, AAV9 and inducible transgenic expression of cTnI-C27 peptide will be studied in vivo and in ex vivo working hearts. Effects on cardiac muscle contractility and heart function will be examined for therapeutic efficacy in normal and diastolic dysfunctional and fibrotic mouse hearts to evaluate the therapeutic potential of cTnI-C27 peptide. Aim 3 is to determine the chronic effects of exogenous cTnI-C27 peptide on cardiac function and remodeling. To develop the cTnI-C27 peptide for the treatment of chronic heart failure, we need to understand the effects of chronic presence of cTnI-C27 peptide on cardiac muscle. We shall examine the therapeutic and side-effects of chronic transgenic expression of cTnI-C27 peptide in normal and failing mouse heart. In vivo and ex vivo cardiac function, tolerance to hemodynamic stresses, and myocardial remodeling will be examined in young and aging mice to collect informative longitudinal data. With combined expertise in myofilament protein structure-function relationships and cardiac physiology and pathophysiology using multi-level experimental approaches, the study of a promising therapeutic peptide of endogenous origin will lay mechanistic and methodologic groundwork for translating a novel myofilament mechanism into a new treatment for diastolic heart failure.

项目名称：心脏肌钙蛋白I c端肽治疗舒张性心力衰竭