Signaling Processes Underlying Cardiovascular Function

描述(由申请人提供)： 该计划项目拨款将整合作为正常和异常心血管功能和发育基础的信号转导的各个方面。该程序在技术上是统一的，在细胞培养和小鼠中使用获得和失去功能的方法。将研究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，以及它们与整体应激反应的交叉点。该计划由4个项目和3个核心组成。项目1：心肌病的致病信号将侧重于了解一般伴侣蛋白α-B晶体蛋白(CryAB)的突变如何在应激反应信号传递过程中影响整体心功能。由于其他每个项目都建议调节特定的信号通路，因此将末端反应(S)与心肌细胞中的全局细胞事件整合起来是很重要的。项目2：心脏发育中的Akt-FoxO途径将研究FoxO亚家族的叉头相关转录因子。这个亚家族的成员参与调节出生后心肌、骨骼肌和平滑肌细胞的增殖、分化和细胞大小的控制。项目3：心脏中的ERK-MAPK信号分支将集中在ERK通路上，ERK通路是MAPK信号通路的三个分支之一。该项目的假设是ERK1/2信号在介导生理性和病理性心肌肥厚中既是必要的，也是充分的。尽管许多研究人员认为情况就是这样，有100多篇报告使用培养细胞来研究这一途径，但仔细阅读文献就会发现，几乎没有关于MEK1-ERK1/2信号在成人心脏中的必要和充分功能的体内报道。项目4：心脏发育和应激适应中的G蛋白受体激酶将探索G蛋白受体激酶(GRKs)，它使配体占据的β-AR磷酸化，从而使它们与G蛋白效应器解偶联，并针对它们进行内化。行政核心(A)将作为组织的重点。组织病理学/生理学核心(B)将为必要的组织学和病理学以及生理学分析提供一个综合的中央设施。腺病毒-心肌细胞核心(C)将为该项目准备病毒、新生大鼠心肌细胞以及胎儿和成年小鼠心肌细胞。

DESCRIPTION (provided by applicant): The Program Project Grant will integrate aspects of signal transduction that underlie normal and abnormal cardiovascular function and development. The Program is unified technically in using the approaches of gain- and loss-of-function in cell culture and in the mouse. Signaling pathways in normal cardiac development and function, the basic biology of cardiac signal transduction, and their intersections with the overall stress response will be studied. The Program consists of 4 Projects and 3 Cores. Project 1: Pathogenic signaling in cardiomyopathy will focus on understanding how mutations in a general chaperone, alpha-B crystallin (CryAB) can affect global cardiac function during stress response signaling. As each of the other Projects proposes to modulate specific signaling pathways, it is important to integrate the end response(s) with global cellular events in the cardiomyocyte. Project 2: The Akt-FoxO pathway in heart development will study the FoxO subfamily of the forkhead-related transcription factors. The members of this subfamily participate in regulating proliferation, differentiation and control of cell size in postnatal cardiac, skeletal and smooth muscle lineages. Project 3: The ERK-MAPK signaling branch in the heart will focus on the ERK pathway, one of the three branches of the MAPK signaling pathway. The hypothesis of the project is that ERK1/2 signaling is both necessary and sufficient in mediating physiologic and pathophysiologic cardiac hypertrophy. Although many investigators assume this is the case, with over 100 reports studying the pathway using cultured cells, a careful reading of the literature shows that almost nothing has been reported in vivo as to the necessary and sufficient functions of MEK1-ERK1/2 signaling within the adult heart. Project 4: G-protein receptor kinases in cardiac development and stress adaptation will explore the G-protein receptor kinases (GRKs), which phosphorylate ligand-occupied beta-AR, thus uncoupling them from G-protein effectors and targeting them for internalization. The Administrative Core (A) will serve as the organizational focus. The HistoPathology/Physiology Core (B) will provide an integrated central facility for the necessary histology and pathology, as well as for the physiological analyses. The Adenovirus-Cardiomyocyte Core (C) will prepare virus, rat neonatal cardiomyocytes and fetal and adult mouse cardiomyocytes for the Projects.