TROPONIN T PHOSPHORYLATION AND CARDIAC HYPERTROPHY

肌钙蛋白 T 磷酸化与心脏肥大

• 批准号: 6208209
• 负责人: MARIUS P SUMANDEA
• 金额: $ 3.24万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-08-01 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6208209
• 关键词: calcium flux; cardiac myocytes; gene mutation; laboratory mouse; microfilaments; muscle contraction; phosphorylation; protein isoforms; protein kinase C; protein structure function; troponin; ventricular hypertrophy

Cardiac myocyte hypertrophy is an essential chronic adaptation, but it eventually becomes maladaptive resulting in the transition from hypertrophy to failure. Our long term objective is to identify mechanisms by which alterations in myofilament protein structure/function relations promote the hypertrophic response and the transition from compensated to decompensated hypertrophy. There is compelling evidence that modifications of the thin filament regulatory proteins, cardiac troponin T (cTnT) and cardiac troponin I (cTnI), either by protein kinase C (PKC) phosphorylation or by switching to a mutant isoform, may be important in the transition between compensated hypertrophy and decompensation. Phosphorylation of cTnT and CTnI depress myofilament force generation and may be maladaptive. Our overall objective is to test the hypothesis that isoform switching of cTnT to mutant forms genetically linked to familial hypertrophic cardiomyopathy (FHC) alters functional effects of PKC dependent phosphorylation of both TnT and cTnI. Our specific aims address the following questions: Aim number 1. What is the relative significance of TnT PKC sites -Thr206, Thr 215, and Thr 295 - on Ca2+-dependent activation of myofilament force, crossbridge kinetics, and economy? Aim number 2. Are functional effects of cTnT or cTnI phosphorylation amplified or repressed in myofilaments containing cTnT-deltaexon 15,16 (missing 27 C- terminal amino acids including Thr 295)? Aim number 3. How is myofilament Ca2+-signaling involving protein-protein interactions of cTnT with CTnI and with cTnC altered by protein phosphorylation? These studies will provide important information relevant to our understanding of heart failure.

心肌细胞肥大是一种必不可少的慢性适应，但最终导致不良适应性导致从肥大到衰竭的过渡。 我们的长期目标是确定肌丝蛋白结构/功能关系改变的机制，促进了肥厚的反应以及从补偿到代偿性肥大的过渡。有令人信服的证据表明，通过蛋白激酶C（PKC）磷酸化或通过切换到突变同类型，对蛋白激酶C（PKC）磷酸化的修饰，心脏肌钙蛋白T（CTNT）T（CTNT）和心脏肌钙蛋白I（CTNI）的修饰可能对补偿超高和转换之间的过渡可能很重要。 CTNT和CTNI的磷酸化降低了肌丝肌的产生，可能是适应不良的。 我们的总体目的是检验以下假设，即CTNT转换为与家族性肥厚性心肌病（FHC）相关的突变体形式（FHC）改变了TNT和CTNI依赖性磷酸化的功能效应。 我们的具体目的解决了以下问题：目标1。在Ca2+依赖性激活肌丝肌，Crossbridge动力学和经济上，TNT PKC站点的相对意义是什么？ 目的2。是否在包含CTNT-DELTAEXON 15,16（包括27个C-末端氨基酸（包括THR 295））的肌细胞膜中放大或抑制CTNT或CTNI磷酸化的功能效应？ 目标数3。肌丝Ca2+信号如何涉及CTNT与CTNI的蛋白质 - 蛋白质相互作用以及通过蛋白质磷酸化改变的CTNC？ 这些研究将提供与我们对心力衰竭的理解有关的重要信息。