ENDOTHELIAL CELL SIGNALING AND CARDIAC ANGIOGENESIS

缺血性心脏病专门研究中心（SCOR）将汇集贝斯以色列女执事医疗中心（BIDMC）和哈佛医学院（HMS）以及马萨诸塞州理工学院健康、科学和技术部（HST）和生物系的临床和基础科学任命的教师。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中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，相当大的重点放在开发新的临床和功能终点需要评估血管生成治疗的疗效。最近的研究已经最终证明血管床和微环境特异性调节内皮细胞功能。因此，有充分的理由预期，所涉及的信号传导事件-来自和去往内皮细胞的信号传导事件也是血管床和器官特异性的。因此，对内皮细胞信号传导的任何研究都应该与当地情况联系起来。考虑到这一概念，SCOR应用中的三个项目旨在评估几个不同水平的内皮细胞信号传导。其中包括：1）肌细胞源性血管生成刺激因子的鉴定和表征; 2）内皮细胞中参与介导bFGF依赖性血管生成的新型syndecan-4依赖性信号通路的分子分析; 3）血管床特异性内皮细胞转录的研究。结合起来，这些项目提供了一个全面的方法，内皮细胞的多样性和由内而外以及由外而内的信号在调节局部过程的作用。该SCOR申请中的临床项目解决了该研究的治疗应用中的两个基本问题-有效局部递送策略的开发和在血管生成治疗的大规模试验中有用的新型临床终点的表征。这些项目得到了核心实验室的支持，这些实验室在大口径和小口径磁共振成像以及转基因小鼠的生成和评估方面提供关键的专业知识。虽然我们的重点主要是心血管应用，但该计划将为内皮细胞生物学，血管生成和信号转导提供广泛的生物学见解，这些生物学见解将与肺，血液和其他疾病相关。

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.