VASCULAR ENDOTHELIAL CADHERIN FUNCTION IN INFLAMMATION

申请人在过去的8年里一直在研究粘膜淋巴细胞归巢和再循环。成就包括在分子和细胞生物学水平上对上皮内淋巴细胞与上皮细胞相互作用的贡献。环境：哈佛大学附属的布里格姆妇女医院是公认的医学研究的领导者，并将提供一个支持性和激励性的环境。导师在血管研究部的实验室可以获得这项研究所需的专业设备和组织。研究：胃炎、溃疡、乳糜泻、克罗恩病、溃疡性结肠炎、肾小球肾炎、间质性肾炎、肾盂肾炎均以炎症细胞活化导致组织损伤为特征。白细胞迁移和伴随的血管通透性增加是炎症反应的关键步骤。因此，器官血管系统的完整性是正常系统功能所必需的，在这些疾病中，内皮屏障必须被破坏才能导致组织损伤。尽管我们对白细胞-内皮细胞粘附和炎症了解甚多，但内皮细胞在调节通透性、白细胞和大分子中所起的作用却知之甚少。血管内皮钙粘蛋白位于内皮粘附和连接处，可能调节单层对白细胞和炎症因子的通透性。本提案的目的是研究ve -钙粘蛋白在血管内皮细胞屏障功能和细胞生长中的作用，通过显性负性机制破坏。使用腺病毒表达系统将实现高效转染。这种方法将允许对粘附连接的一个组成部分进行特异性破坏，并允许对内皮特定功能进行后续分析。这些技术将被用于探索不同血管床内皮中粘附连接的功能及其对炎症的贡献。这些拟议的研究有望更好地理解内皮粘附连接在正常和疾病条件下的作用，并可能导致新的治疗方法和干预靶点。

Candidate: The applicant has researched mucosal lymphocyte homing and recirculation for the past 8 years. Accomplishments include contributions at both molecular and cell biological levels to interaction of intra- epithelial lymphocytes with epithelial cells. Environment: Brigham and Women's hospital, affiliated with Harvard University, is recognized as a leader in medical research, and will provide a supportive and stimulating environment. The mentor's lab at the Vascular Research Division has access to specialized equipment and tissues necessary for this research. Research: Gastritis, ulceration, celiac sprue, Crohn disease and ulcerative colitis, glomerulonephritis, interstitial nephritis and pyelonephritis are all characterized by the activation of inflammatory cells leading to tissue injury. Leukocyte transmigration and accompanying increased vascular permeability are critical steps during the inflammatory response. Thus, integrity of the organ vasculature is necessary for normal system function, and the endothelial barrier must be breached to lead to tissue injury in these diseases. Although much is known about leukocyte-endothelial adhesion and inflammation, less information is available concerning the role played by endothelial cells in regulating permeability and leukocytes and macromolecules. Vascular endothelial cadherin is located at endothelial adherens and junctions and may regulate monolayer permeability to leukocytes and inflammatory factors. The objective of this proposal is to study the role of VE-cadherin in barrier function and cell growth in vascular endothelial cells by disruption via a dominant negative mechanism. A high efficiency if transfection will be achieved using an adenoviral expression system. This approach will allow specific disruption of one component of the adherens junction, and allow subsequent analysis of endothelial specific functions. These techniques will be used to probe the function of adherens junctions in endothelium from various vascular beds and their contribution to inflammation. The proposed studies are anticipated to allow a better understanding of the role of endothelial adherens junctions in normal and disease conditions, and may lead to novel therapeutic approaches and targets for intervention.