VASCULAR ENDOTHELIAL CADHERIN FUNCTION IN INFLAMMATION

炎症中的血管内皮钙粘蛋白功能

• 批准号: 6342413
• 负责人: SUNIL K SHAW
• 金额: $ 9.29万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-03-15 至 2002-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6342413
• 关键词: cadherins; cell cell interaction; cell growth regulation; cell migration; epitope mapping; human subject; inflammation; laboratory mouse; leukocytes; molecular cloning; monoclonal antibody; tissue /cell culture; transfection; vascular endothelium; vascular endothelium permeability

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.

候选人：申请人在过去的8年中研究了粘膜淋巴细胞的归纳和再循环。成就包括分子和细胞生物学水平的贡献，对上皮淋巴细胞与上皮细胞的相互作用。环境：存在于哈佛大学的杨百翰和妇女医院被公认为医学研究领域的领导者，并将提供支持性和刺激性的环境。血管研究部门的导师实验室可以使用本研究所需的专门设备和组织。研究：胃炎，溃疡，乳糜泻，克罗恩病和溃疡性结肠炎，肾小球肾炎，间质肾炎和肾盂肾炎的特征都以炎性细胞的激活导致组织损伤。白细胞传播和随附的血管通透性增加是炎症反应期间的关键步骤。因此，器官脉管系统的完整性对于正常系统功能是必需的，并且必须破坏内皮屏障以导致这些疾病的组织损伤。尽管对白细胞 - 内皮粘附和炎症知之甚少，但有关内皮细胞在调节渗透性和白细胞和大分子中所起的作用的信息较少。血管内皮钙粘着蛋白位于内皮粘附剂和交界处，可能调节对白细胞和炎症因子的单层渗透性。该提案的目的是通过通过显性负机制破坏VE-钙粘蛋白在血管内皮细胞中屏障功能和细胞生长中的作用。如果使用腺病毒表达系统实现转染将获得高效率。这种方法将允许对粘附连接的一个组成部分进行特定破坏，并允许对内皮特定功能进行后续分析。这些技术将用于探测各种血管床中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，并可能导致新颖的治疗方法和干预目标。