ENDOTHELIAL CELL SIGNALING AND CARDIAC ANGIOGENESIS

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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.