Normal & Pathologic Mechanisms Of Inflammation /Immunity

普通的

• 批准号: 6814285
• 负责人: SHARON M WAHL
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF DENTAL & CRANIOFACIAL RESEARCH
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6814285
• 关键词: apoptosis; arthritis; asthma; autoimmune disorder; autoimmunity; cellular pathology; cytokine; gene expression; gene targeting; genetically modified animals; human tissue; immunity; immunopathology; immunoregulation; inflammation; laboratory mouse; molecular pathology; transforming growth factors

Research in this program is focused on the basic mechanisms by which the host mobilizes and modulates cellular inflammatory reactions in defense against foreign antigens and infectious agents. In a multi-disciplinary approach, mechanisms of integrin adhesion, chemotaxis, signaling, mediator synthesis and apoptosis are explored in vitro and extended into experimental animal models (bacteria induced rodent arthritis; knockout and transgenic mice) for in vivo analysis. In addition, human conditions of chronic inflammatory disease in response to foreign implants, infectious pathogens, or of unknown etiology are explored at the cellular, molecular and biochemical levels. Understanding the mechanisms which control normal immune cell recruitment, activation and/or deletion and the switch to pathogenesis underlies the development of strategies for modulating chronic pathogenic inflammatory diseases. In experimental animal models, we have characterized the immunopathology through phenotypic, functional and morphologic parameters, in addition to DNA microarrays and ribonuclease protection assays, to identify targets for therapeutic intervention including leukocyte adhesion, signal transduction, cytokines, proteases, and nitric oxide. New insights into the regulation of immune function through CD4+CD25+ regulatory T cells which express TGF-beta on their surface raise the prospect of novel approaches to controlling immunological tolerance. This key population of suppressor T cells is important in prevention and inhibition of autoimmune diseases, allotransplant rejection and in cancer pathogenesis. Another endogenous immunoregulatory molecule, SLPI, was found to be instrumental in host defense to an intracellular parasite and protection from allergen-induced asthma. Delineation of the immune response in SLPI deficent mice will help define the role of SLPI in innate and adaptive immunity and its potential as a therapeutic agent in the treatment of infectious and inflammatory diseases.

这个项目的研究重点是宿主动员和调节细胞炎症反应以防御外来抗原和感染性物质的基本机制。在一种多学科的方法中，在体外探索整合素的黏附、趋化、信号、介体合成和细胞凋亡的机制，并扩展到实验动物模型(细菌诱导的啮齿动物关节炎、基因敲除和转基因小鼠)进行体内分析。此外，还从细胞、分子和生物化学水平探讨了人类慢性炎症性疾病对外来植入物、感染性病原体或不明原因的反应情况。了解控制正常免疫细胞募集、激活和/或缺失以及向发病机制转变的机制是制定调控慢性致病性炎症性疾病的策略的基础。在实验动物模型中，除了DNA芯片和核糖核酸酶保护分析外，我们还通过表型、功能和形态参数来表征免疫病理学，以确定治疗干预的靶点，包括白细胞黏附、信号转导、细胞因子、蛋白酶和一氧化氮。通过表面表达转化生长因子-β的CD4+CD25+调节性T细胞调节免疫功能的新见解增加了控制免疫耐受的新方法的前景。这一关键的抑制性T细胞群在预防和抑制自身免疫性疾病、同种异体移植排斥反应和癌症发病机制中具有重要作用。另一种内源性免疫调节分子SLPI被发现在宿主防御细胞内寄生虫和保护过敏原诱导的哮喘方面发挥作用。描述SLPI缺陷小鼠的免疫反应将有助于确定SLPI在先天性和获得性免疫中的作用，以及它作为治疗感染性和炎症性疾病的潜在药物的潜力。