Integrated Mechanisms of Cardiac Maladaptation

这里提出的实验继续在四个项目之间进行高度互动和协同作用 由三个内核支持。这些项目和核心通过实验的中心主题联系在一起，这一主题 检验以下假设：肌节重塑是从 代偿性肥厚到失代偿和症状性心力衰竭。我们广义地定义 作为翻译后修饰的肌节重塑，亚型群体的转移，以及 与其他信号通路相关的肌瘤蛋白。项目1(R.约翰·索拉罗)是《分子》 心脏肌节中的信号传递“；项目2(布伦达·罗素)为”机械活动与心肌细胞“ 重塑“，它检验了重塑反应受强度调节的假设 机械刺激和它们之间的间隔。项目3(彼得·巴特里克)是《萨克瑞克》 修改和进行性心脏适应不良“，项目4(Pieter De Tombe)是”分子“ 心力衰竭时肌丝功能障碍的机制“，这验证了上调表达的假说 蛋白激酶C的活性和肌瘤靶标的特异性磷酸化会导致失代偿。这些 4个项目得到行政、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在正常和失败制剂研究中的应用 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新的见解。

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.