VASCULAR ENDOTHELIAL CADHERIN FUNCTION IN INFLAMMATION

候选人：申请人在过去8年中研究了粘膜淋巴细胞归巢和再循环。研究成果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。工作环境：附属于哈佛大学的布里格姆妇女医院被公认为医学研究的领导者，并将提供一个支持和激励的环境。导师在血管研究部的实验室可以使用这项研究所需的专用设备和组织。调研：胃炎、溃疡、口炎性腹泻、克罗恩病和溃疡性结肠炎、肾小球肾炎、间质性肾炎和肾盂肾炎的特征都是炎性细胞活化导致组织损伤。白细胞迁移和伴随的血管通透性增加是炎症反应过程中的关键步骤。因此，器官脉管系统的完整性对于正常的系统功能是必需的，并且内皮屏障必须被破坏以导致这些疾病中的组织损伤。虽然对白细胞-内皮细胞粘附和炎症了解很多，但关于内皮细胞在调节渗透性和白细胞及大分子中所起作用的信息较少。血管内皮钙粘蛋白定位于内皮粘附和连接处，并可调节单层细胞对白细胞和炎性因子的通透性。本提案的目的是通过显性负性机制研究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。使用腺病毒表达系统将实现高效率的转染。这种方法将允许特异性破坏粘附连接的一种组分，并允许随后分析内皮特异性功能。这些技术将用于探测各种血管床内皮中粘附连接的功能及其对炎症的贡献。 预计拟议的研究可以更好地了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目标。

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.