STRUCTURE FUNCTION STUDIES OF MUSCLE AND HEART

肌肉和心脏的结构功能研究

• 批准号: 3156648
• 负责人: JAGDISH GULATI
• 金额: $ 23.11万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 1992
• 资助国家: 美国
• 起止时间: 1992-09-18 至 1996-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3156648
• 关键词: calcium binding protein; cardiotonic agents; chemical chain length; computer simulation; genetic manipulation; hamsters; heart contraction; heart failure; heart pharmacology; laboratory rabbit; molecular biology; muscle tension; myocardium disorder; protein structure function; sarcomeres; striated muscles; troponin; western blottings

The broad aim of this research is to establish the molecular basis of skeletal and cardiac muscle assembly and function in the normal tissue and in heart failure. The major present goals are (1) to use molecular genetics to study the length dependency of cardiac muscle (Starling's law of the heart) by defining the amino acid residues responsible for the length sensing mechanism. Specific manipulations of the structure of TnC will be correlated with alterations in the cardiac and skeletal length-tension curves. (2) We propose to investigate the basis of cooperativity in the Ca2+-switching processes of the thin filaments in cardiac muscle. Also, by examining the interactions of force modifying compounds, such as TFP as well as cardiotonic agents, with the Ca-binding proteins and their genetic variants, we will examine whether the hydrophobic residues of TnC participate in setting the cooperativity level in the Ca-force relations in muscle. In addition we will study the specific role of the central helix in TnC and calmodulin in the switching mechanisms. In particular, we propose to determine whether the central linker between the N- and C-terminal lobes is essential to function. Further, by combining the mutation studies with computer simulations, we will examine whether the bending of the central helix that could cause compaction of the molecule, is essential for the molecular dynamics related to ligand binding, and also whether the highly conserved arginine residues are implicated in this function. (3) We also propose to characterize the properties of cofactor-B. Cofactor-B, discovered in this lab, is a protein essential for reconstitution of extracted fibers. Our goals are to purify, clone, mutate, determine isoformic diversity, and study the expression of cofactor-B in normal tissue as well as during the development of cardiomyopathy of the Syrian hamster. A major hypothesis is suggested that cofactor-B controls the link between the weak and strong cross-bridge states.

本研究的主要目的是建立分子基础