Signaling Processes Underlying Cardiovascular Function

描述（由申请人提供）：本项目“心血管功能的信号传导过程”的中心目标是将我们对心脏功能的特定信号传导途径整合到正常和致病性纤维化的研究扩展。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3个项目将致力于确定在手术、药理学和遗传诱导的心脏病中介导肌成纤维细胞转化和长期纤维化的成纤维细胞信号通路的确切身份。所有的项目也将试图确定对过程的致病后果产生有利影响的治疗窗口。我们的小组由3个项目负责人和4个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。方法的通用性和跨项目模型的无缝使用强调了PPG基础上的协同和协作。该项目的目标是证明基于成纤维细胞的信号通路在心脏病中的重要性。项目1的题目是：心肌病中的纤维化信号。儿科学教授杰弗里·罗宾斯博士将重点研究以成纤维细胞为基础的TGF -信号传导过程在肌瘤性和非肌瘤性疾病的纤维化反应中起关键作用的中心假设。项目2的题目是：Wnt/¿-catenin信号和心脏纤维化。儿科教授Katherine Yutzey博士将验证Wnt/¿-catenin信号传导促进间质成纤维细胞的正常发育，并有助于成人心血管疾病的病理性间质纤维化的假设。项目3的题目是：TGF¿信号及其在心脏纤维化中的作用。Jeffery Molkentin博士。她将重点研究外科手术导致的心脏病发展过程中，心脏成纤维细胞中典型和非典型TGF -¿信号。假设成纤维细胞通过选择信号通路对TGF -¿和其他细胞因子作出反应，促进纤维化和适应性不良重塑。这些项目由3个核心支持：核心A：行政核心；核心B：生理学核心和核心C：成像细胞培养核心。（摘要结束）

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)