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Mechanism of Calcium Regulation in Striated Muscle

横纹肌钙调节机制

基本信息

批准号：
7241612
负责人：
Terence Tao
金额：
$ 70.08万
依托单位：
BOSTON BIOMEDICAL RESEARCH INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-06-01 至 2009-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7241612
关键词：
Mechanism Calcium Regulation Striated Muscle

项目摘要

DESCRIPTION (provided by applicant): Muscle contraction is one of the fundamental biological processes. In spite of many years of intense research, the two major questions, the mechanisms of force generation and its regulation, remain incompletely understood. The long term objective of this project is to decipher the molecular mechanism for the regulation of striated (skeletal and cadiac) muscle contraction via Ca 2+, troponin and tropomyosin. The specific aims for this proposal are: 1) To decipher the mechanism whereby attachment of troponin I to actin inhibits muscle contraction in the absence of Ca2+. 2) To decipher the mechanism whereby the movement of tropomyosin in the F-actin filament gives rise to inhibition or activation of muscle contrction. 3) To determine the functional role of troponin T in thin filament regulation. The principal techniques will be site-directed mutagenesis, disulfide crosslinking, photocrosslinking and Forster resonance energy transfer (FRET). The results will make major contributions not only to the muscle field, but also to areas in signal transduction that involve regulation by Ca 2+. Findings derived from this project will be relevant to the prevention, diagnosis and cure of certain neuromuscular diseases. Cardiac and skeletal muscle thin filament proteins share a great deal of similarity in amino acid sequence and function. Cardiac Tn subunits have been used as markers for heart failure. Point mutations in the cardiac thin filament proteins have been implicated in certain cardiomyopathies. Thus our findings here will also be relevant to ischemic infarction and familial hypertrophic cardiomyopathy.

描述（由申请人提供）：肌肉收缩是基本的生物学过程之一。尽管多年来进行了深入的研究，但两个主要问题，即力的产生及其调节机制，仍然没有完全弄清楚。本项目的长期目标是通过Ca 2+、肌钙蛋白和原肌球蛋白来解释横纹肌（骨骼肌和心脏）收缩的分子机制。该建议的具体目标是：1）解释肌钙蛋白I与肌动蛋白的连接在缺乏Ca 2+的情况下抑制肌肉收缩的机制。2)解释原肌球蛋白在F-肌动蛋白丝中的运动引起肌肉收缩抑制或激活的机制。3)确定肌钙蛋白T在细肌丝调节中的功能作用。主要技术将是定点诱变，二硫键交联，光交联和福斯特共振能量转移（FRET）。这一结果不仅对肌场，而且对涉及Ca 2+调节的信号转导领域都有重要贡献。该项目的研究结果将与某些神经肌肉疾病的预防、诊断和治疗有关。心肌和骨骼肌细丝蛋白在氨基酸序列和功能上具有很大的相似性。心脏Tn亚单位已被用作心力衰竭的标志物。心脏细丝蛋白的点突变与某些心肌病有关。因此，我们的发现也将与缺血性梗死和家族性肥厚型心肌病有关。