Molecular Physiolog of Myocardial Troponin I Variants.

 描述（申请人提供）：肌节是心脏的分子马达。心脏的收缩是由调节蛋白，特别是肌钙蛋白I， 肌节的细丝。心肌肌钙蛋白I的功能受到多种翻译后修饰的影响，包括我们最近发现的新修饰。肌钙蛋白I的修饰在心力衰竭和肥厚型心肌病（一种肌节蛋白的遗传性疾病）中发生改变。研究者的实验室对肌丝蛋白的翻译后变化有着长期的兴趣，这种变化会导致收缩和舒张功能障碍。本实验室将继续致力于理解位点特异性翻译后修饰的精确定量和肌钙蛋白I特异性修饰的功能意义。本提案将检验以下假设：肥厚型心肌病中的翻译后修饰和疾病等位基因特异性蛋白表达是疾病的一些病理生理表现的基础，肌钙蛋白I上的新磷酸化位点有助于心力衰竭和肥大中的收缩病理生理学。目的包括翻译蛋白质组学实验，以量化突变等位基因表达和肥厚型心肌病相关的磷酸化改变，并将这些直接与人类心肌细胞的功能联系起来。两个新的肌钙蛋白I磷酸化，发现在以前的周期，这是相关的心力衰竭表型，也将进行功能评价。这些研究将产生新的治疗策略，可能针对和补偿肥厚型以及扩张型心肌病和心力衰竭的这些功能变化。

 DESCRIPTION (provided by applicant): The sarcomere is the molecular motor of the heart. Contraction of the heart is finely tuned by regulatory proteins and in particular troponin I on the thin filament of the sarcomere. Cardiac troponin I function is modified by multiple post-translational modifications, including novel modifications we recently discovered. Modifications of troponin I are altered in heart failure and hypertrophic cardiomyopathy, a genetic disease of sarcomeric proteins. The investigator's laboratory has a long-term interest in post-translational changes in the myofilament proteins which contribute to systolic and diastolic dysfunction. The laboratory continues to focus on understanding the precise quantification of site specific post-translational modifications and the functional significance of specific modifications of troponin I This proposal will test hypotheses that post- translational modifications and disease allele specific protein expression in hypertrophic cardiomyopathy underlie some of the pathophysiologic manifestations of disease, and that novel phosphorylation sites on troponin I contribute to contractile pathophysiology in heart failure and hypertrophy. The aims include translational proteomics experiments to quantify mutant allele expression and hypertrophic cardiomyopathy associated phosphorylation alterations and linking these directly to function in human cardiomyocytes. Two novel TnI phosphorylations, discovered in the prior cycle, which are relevant to the heart failure phenotype, will also be functionally evaluated. These studies wil produce new therapeutic strategies which may target and compensate for these functional changes in hypertrophic as well as dilated cardiomyopathy and heart failure.