Signaling Processes Underlying Cardiovascular Function

描述(由申请人提供)： 该计划项目拨款将整合信号转导的各个方面， 心血管功能有正常和异常之分。函数增益和损耗 方法包括细胞培养、基因打靶和心脏特异性 转基因。正常心脏发育和功能中的信号通路， 心脏信号转导的基本生物学及其在心肌细胞中的作用 将对最终目标进行研究。该方案包括4个子项目和3个 核心。子项目1：收缩蛋白的磷酸化和功能 重点是肌原纤维蛋白，探索收缩装置是如何 被调整到与当前条件相匹配。利用心脏特异性转基因， 蛋白质中的相关位点被修饰，使得它们不能 磷酸化，或表现为长期磷酸化，将会 取代内源性TnI或MyBP-C蛋白补体。子项目2： 钙调神经磷酸酶/NFAT通路在心脏发育中的调控作用 控制差异基因表达和形态发生的级联反应 心脏发育以确定钙调神经磷酸酶信号是否通过NFAT家族 转录因子驱动收缩蛋白的程序性变化 心脏发育过程中的基因表达。子项目3：ERK-MAPK信号 心脏分支将探索ERK-MAPK通路在诱导 心肌肥厚和促进对细胞凋亡刺激的保护。这个 MEK1显性阴性小鼠和ERK1基因敲除小鼠的肥大潜能 将被描述为。ERK-MAPK通路在心脏保护中的作用 将分析MEK1-ERK1/2的转录机制 信号转导心肌肥大。子项目4：Rab GTPase蛋白 心脏疾病中的转运调节。Rab蛋白家族控制 亚细胞蛋白转运与心肌RAb的个体作用 将使用功能增益方法在心脏中探索蛋白质 包括心肌细胞和转基因动物。行政核心(A) 将作为组织的焦点，组织病理学/生理学核心 (B)将为必要的组织学提供综合的中央设施 和病理学，以及生理分析。腺病毒核心 (C)将为次级项目2、3和4以及新生大鼠准备病毒 心肌细胞，这将是子项目3和4所需的。

DESCRIPTION (provided by applicant): The Program Project Grant will integrate aspects of signal transduction that underlie normal and abnormal cardiovascular function. Gain- and loss-of-function approaches include cell culture, gene targeting and cardiac-specific transgenesis. Signaling pathways in normal cardiac development and function, the basic biology of cardiac signal transduction, as well as the actions on the final targets will be studied. The Program consists of 4 Subprojects and 3 Cores. Subproject 1: Phosphorylation and function of the contractile proteins focuses on the myofibrillar proteins, exploring how the contractile apparatus is tuned to match prevailing conditions. Using cardiac specific transgenesis, proteins in which the relevant sites are modified such that they cannot be phosphorylated, or act as if they were chronically phosphorylated, will replace the endogenous TnI or MyBP-C protein complements. Subproject 2: The calcineurin/NFAT pathway in heart development will explore the regulatory cascades that control differential gene expression and morphogenesis of the developing heart to determine if calcineurin signaling through the NFAT family of transcription factors drives programmatic changes in contractile protein gene expression during cardiac development. Suproject 3: The ERK-MAPK signaling branch in the heart will explore the ERK-MAPK pathway's role in inducing cardiac hypertrophy and promoting protection from apoptotic stimuli. The hypertrophic potential of MEK1 dominant negative mice and ERK1 knockout mice will be characterized. The role ERK-MAPK pathway's role in cardioprotection will be analyzed as will the transcriptional mechanism whereby MEK1-ERK1/2 signaling mediates cardiac hypertrophy. Subproject 4: Rab GTPase protein transport regulation in heart disease. The Rab protein family controls subcellular protein trafficking and the individual actions of myocardial Rab proteins will be explored in the heart using gain-of-function approaches in both cardiomyocytes and in transgenic animals. The Administrative Core (A) will serve as the organizational focus, The Histo-Pathology/Physiology Core (B) will provide an integrated central facility for the necessary histology and pathology, as well as for the physiological analyses. The Adenovirus Core (C) will prepare virus for subprojects 2, 3 and 4, and neonatal rat cardiomyocytes, which will be needed for subprojects 3 and 4.