Integrated Mechanisms of Cardiac Maladaptation

心脏适应不良的综合机制

• 批准号: 7822212
• 负责人: R John Solaro
• 金额: $ 1.5万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-01 至 2010-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7822212
• 关键词: Integrated; Mechanisms; Cardiac; Maladaptation

Experiments proposed here continue highly interactive and synergistic interactions among four projects supported by three cores. The projects and cores are linked by a central theme of experiments, which test the hypothesis that sarcomeric remodeling is a critical determinant of the transition from compensated hypertrophy to decompensation and symptomatic heart failure. We broadly define sarcomeric remodeling as post-translational modifications, shifts in isoform population, and shuttling of sarcomeric associated proteins to other signaling pathways. Project 1 (R. John Solaro) is "Molecular Signaling in Cardiac Sarcomeres"; Project 2 (Brenda Russell) is" Mechanical Activity and Myocyte Remodeling ", which tests the hypothesis that the remodeling responses are regulated by the strength of mechanical stimuli and the intervals between them. Project 3 (Peter Buttrick) is " Sarcomeric Modifications and Progressive Cardiac Maladaptation", and Project 4 (Pieter de Tombe) is "Molecular Mechanisms of Myofilament Dysfunction in Heart Failure", which tests the hypothesis that up-regulation of protein kinase C and specific phosphorylation of sarcomeric targets leads to decompensation. These 4 projects are supported by Administrative, Animal, and Analytical Biochemistry Cores. Approaches include structural, mechanical and proteomic approaches in studies of normal and failing preparations at the level of proteins, single myofibrils, cells, muscles, and hearts. Data from these experiments provide novel insights into the mechanisms of heart failure and potential therapies.

这里提出的实验继续四个项目之间的高度互动和协同作用 由三个核心支持。这些项目和核心是由一个中心主题的实验， 检验这一假设，即肌节重塑是从 代偿性肥大到失代偿和症状性心力衰竭。我们广泛定义 翻译后修饰引起的肌节重塑、同种型群的变化以及 肌节相关蛋白与其他信号通路的联系。项目1（R.约翰·索拉罗）是《分子 心脏肌节的信号传导”;项目2（Brenda Russell）是”机械活动和肌细胞 重塑“，其检验了重塑反应受强度调节的假设 以及它们之间的间隔。项目3（彼得Buttrick）是“肉瘤 修改和进行性心脏适应不良”，项目4（彼得·德·汤贝）是“分子 心力衰竭中肌丝功能障碍的机制”，该研究验证了上调 蛋白激酶C的磷酸化和肌节靶点的特异性磷酸化导致失代偿。这些 4个项目得到了行政、动物和分析生物化学核心的支持。方法 包括结构、机械和蛋白质组学方法，用于研究正常和失败制剂 在蛋白质、单个肌原纤维、细胞、肌肉和心脏的水平上。来自这些实验的数据 为心力衰竭的机制和潜在的治疗方法提供了新的见解。