Signaling Processes Underlying Cardiovascular Function

描述（由申请人提供）： 该计划项目赠款将整合信号转导方面， 是正常和异常心血管功能的基础。功能增益和功能丧失 方法包括细胞培养、基因靶向和心脏特异性 转基因正常心脏发育和功能的信号通路， 心脏信号转导的基础生物学，以及对 将研究最终目标。该计划包括4个子项目和3个 丹子项目1：收缩蛋白的磷酸化和功能 重点是肌原纤维蛋白，探索收缩装置如何 都能适应当前的环境使用心脏特异性转基因， 蛋白质，其中相关位点被修饰，使得它们不能被 磷酸化的，或者表现得好像它们是慢性磷酸化的， 替代内源性TnI或MyBP-C蛋白补体。次级项目2： 钙调神经磷酸酶/NFAT通路在心脏发育中的调节作用 级联反应控制差异基因表达和形态发生的 开发心脏，以确定是否通过NFAT家族的钙调神经磷酸酶信号传导 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信号转导 心脏分支的研究将探讨ERK-MAPK通路在诱导心肌细胞凋亡中的作用。 心脏肥大和促进保护免受凋亡刺激。的 MEK 1显性阴性小鼠和ERK 1基因敲除小鼠肥大潜能 将被定性。ERK-MAPK通路在心肌保护中的作用 将分析MEK 1-ERK 1/2的转录机制， 信号传导介导心脏肥大。子项目4：Rab GT3蛋白 心脏病中的转运调节Rab蛋白家族控制 心肌Rab的亚细胞蛋白运输和个体作用 将使用功能获得方法在心脏中探索蛋白质， 在心肌细胞和转基因动物中。行政核心（A） 将作为组织的重点，组织病理学/生理学核心 (B)将为必要的组织学提供一个综合的中心设施， 和病理学，以及生理分析。腺病毒核心 (C)将为子项目2、3和4以及新生大鼠制备病毒 心肌细胞，这将需要为子项目3和4。

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.