Signaling Processes Underlying Cardiovascular Function

描述（由申请人提供）：我们的计划项目资助“心血管功能背后的信号传导过程”的中心目标是将我们的研究扩展到整合心脏功能背后的特定信号传导途径，以实现正常和致病性纤维化。核心假设是，以成纤维细胞为中心的信号通路对许多心血管疾病和心力衰竭的纤维化过程至关重要。关于成纤维细胞本身是否以及如何导致心脏病，确实缺乏数据和理解。这三个项目将致力于确定成纤维细胞内信号通路的确切身份，这些信号通路介导手术、心脏病和遗传诱导的心脏病中的肌成纤维细胞转化和长期纤维化。所有项目还将试图确定治疗窗口，以有利地影响过程的致病后果。我们的团队由3名项目负责人和4名核心导向的调查员组成，他们有持续和富有成效的合作记录。方案设计小组的协同作用和协作体现在方法的通用性和各项目模型的无缝使用上。该计划的目标是证明基于成纤维细胞的信号通路在心脏疾病中的重要性的概念验证。项目1的标题是：心肌病中的纤维化信号传导。杰弗里·罗宾斯博士儿科教授，将专注于测试中心假设，即成纤维细胞为基础的TGF信号传导过程在肌节为基础和非肌节为基础的疾病的纤维化反应中发挥关键作用。项目2的题目是：Wnt/β-catenin signaling and cardiac fibrosis。凯瑟琳·尤齐（Katherine Yutzey），博士儿科教授，将测试的假设，Wnt/连环蛋白信号促进间质成纤维细胞的正常发育，也有助于病理性间质纤维化在成人心血管疾病。项目3的标题是：TGF β信号传导及其在心脏纤维化中的作用。Jeffery Molkentin博士，儿科教授，将专注于在心脏疾病的发展过程中，心脏成纤维细胞的经典和非经典TGF？信号传导诱导的手术干预的结果。假设成纤维细胞通过选择信号通路对TGF β和其他细胞因子做出反应，促进纤维化和适应不良的重塑。这些项目由3个核心支持：核心A：行政核心;核心B：生理核心和核心C：成像细胞培养核心。(End摘要）

DESCRIPTION (provided by applicant): The central objective of our Program Project Grant "Signaling Processes Underlying Cardiovascular Function," is to extend our investigation of integrating specific signaling pathways underlying cardiac function to normal and pathogenic fibrosis. The central hypothesis is that the signaling pathways centered in the fibroblast are critical to the fibrotic processes characteristic of so much cardiovascular disease and heart failure. There is truly a remarkable lack of data and understanding as to if and how fibroblasts themselves contribute to cardiac disease. The 3 Projects will direct their efforts at determining the exact identity of the signaling pathways within fibroblasts that mediate myofibroblast transformation and longstanding fibrosis in surgically, pharmacologically- and genetically-induced cardiac disease. All of the Projects will also attempt to identify therapeutic windows for impacting favorably on the processes' pathogenic consequences. Our group consists of 3 Project Leaders and 4 Core-oriented investigators who have a track record of sustained and productive collaboration. The synergy and collaborations that underlie the PPG are underscored by the commonality of approach and the seamless use of models across the Projects. The goal of this Program is to prove proof-of-concept of fibroblast-based signaling pathways' importance in cardiac disease. Project 1's title is: Fibrotic signaling in cardiomyopathy. Jeffrey Robbins, Ph.D., Professor of Pediatrics, will focus on testing the central hypothesis that TGF¿ signaling processes that are fibroblast-based play a critical role in the fibrotic response in sarcomere-based and nonsarcomere- based disease. Project 2's title is: Wnt/¿-catenin signaling and cardiac fibrosis. Katherine Yutzey, Ph.D., Professor of Pediatrics, will test the hypothesis that Wnt/¿-catenin signaling promotes normal development of interstitial fibroblasts and also contributes to pathologic interstitial fibrosis in adult cardiovascular disease. Project 3's title s: TGF¿ signaling and its role in cardiac fibrosis. Jeffery Molkentin, PhD., Professor of Pediatrics, will focus on canonical and non-canonical TGF¿ signaling in the cardiac fibroblast during cardiac disease development induced as a result of surgical intervention. The hypothesis is that the fibroblast responds to TGF¿ and other cytokines through select signaling pathways in promoting fibrosis and maladaptive remodeling. These projects are supported by 3 Cores: Core A: The Administrative Core; Core B: The Physiology Core and Core C: The Imaging-Cell Culture Core. (End of Abstract)