ENDOTHELIAL CELL SIGNALING AND CARDIAC ANGIOGENESIS

缺血性心脏病专业研究中心(SCOR)将汇集贝丝以色列女执事医疗中心(BIDMC)、哈佛医学院(HMS)以及麻省理工学院卫生、科学和技术部(HST)和生物系的临床和基础科学职位的教职员工。这项研究的主要目标是为缺血性心脏病的新治疗方法奠定基础，这将是我们设计刺激患病心脏侧支血管生长的新方法的核心。因此，该计划结合了血管生物学和分子医学的基础、应用和临床研究。此外，对评估血管生成治疗效果所需的新的临床和功能终点的开发也给予了相当的重视。最近的研究已经确凿地证明了血管床和环境对内皮细胞功能的特异性调节。因此，我们完全有理由预计，涉及的信号事件--无论是去往内皮细胞还是来自内皮细胞--也是特定于血管床和器官的。因此，任何对内皮细胞信号转导的研究都应该与当地的背景相联系。考虑到这一概念，SCOR应用程序中的三个项目旨在评估几个不同水平的内皮细胞信号。这些包括：1)肌源性血管生成刺激因子的鉴定；2)内皮细胞中一种新的Syndecan-4依赖的信号通路的分子分析，该信号通路参与介导bFGF依赖的血管生成；3)血管床特异性内皮细胞转录的研究。结合起来，这些项目提供了一种全面的方法来研究内皮细胞多样性和由内向外以及由外向内信号在局部过程调控中的作用。这一SCOR应用程序的临床项目解决了这项研究在治疗应用中的两个基本问题--开发有效的局部给药策略和表征新的临床终点，这将有助于血管生成治疗的大规模试验。这些项目得到了核心实验室的支持，这些实验室提供大小口径磁共振成像以及转基因小鼠的生成和评估方面的关键专业知识。虽然我们的重点主要是心血管应用，但这个项目将提供对内皮细胞生物学、血管生成和与肺、血液和其他疾病相关的信号转导的广泛生物学见解。

The Specialized Center of Research (SCOR) in Ischemic Heart Disease will bring together faculty with clinical and basic science appointments at the Beth Israel Deaconess Medical Center (BIDMC) and Harvard Medical School (HMS) as well as Division of Health, Science and Technology (HST) and Department of Biology at the Massachusetts Institute of Technology. The Principal goal of this research is to lay down a foundation for new therapeutic approaches to the ischemic heart disease that will be at the core of our ability to design novel ways of stimulating collateral vessel growth in the diseased heart. Thus, the program combines basic, applied, and clinical research in vascular biology and molecular medicine. In addition, considerable emphasis is placed on the development of novel clinical and functional endpoints needed to assess the efficacy of angiogenic therapy. Recent investigations have conclusively demonstrated vascular bed- and milieu-specific regulation of endothelial cell function. Thus, there is every reason to expect that signaling events involved- both to and from endothelial cells are also vascular-bed and organ specific. Therefore, any investigation of endothelial cell signaling should be linked to the local context. With this concept in mind, three projects in this SCOR application are designed to assess endothelial cell signaling at several different levels. These include: 1) Identification and characterization of myocyte-derived stimulators of angiogenesis; 2) Molecular analysis of a novel syndecan-4-dependent signaling pathway in endothelial cells that is involved in mediation of bFGF-dependent angiogenesis; 3) The study of vascular bed-specific endothelial cell transcription. In combination, these projects provide a comprehensive approach to the role of endothelial cell diversity and inside-out as well outside-in signaling in regulation of local processes. The clinical project in this SCOR application addresses two fundamental issues in therapeutic application of this research- Development of effective local delivery strategies and characterization of novel clinical end-points that would be useful in large scale trials of angiogenic therapy. These projects are supported by Core laboratories that provide critical expertise in large and small bore magnetic resonance imaging and generation and evaluation of transgenic mice. Although our focus is primarily on cardiovascular applications, this program will provide broad biological insights into endothelial cell biology, angiogenesis and signal transduction that will be relevant to lung, blood and other diseases.