ROLE OF THE FAS/FAS LIGAND SYSTEM IN APOPTOSIS AFTER ENVIRONMENTAL TRAUMA

Lpr和gld小鼠的表型和功能异常类似 人SLE由于Fas和Fas配体（Fas L）凋亡基因异常， 分别 细胞凋亡是细胞程序性死亡的一种形式， 必要的消除自身反应性淋巴细胞从 免疫系统 令人惊讶的发现是Fas与辐射有关- 诱导的细胞凋亡提示Fas/Fas L系统在 在环境创伤后删除细胞。 该提案将定义 Fas/Fas L在γ射线照射后细胞凋亡中作用 术语体外培养系统。 Fas表达的调控 正常和lpr小鼠的损伤细胞将通过检测Fas来研究 表达和转录。 体内短期 嵌合体实验和体内细胞毒性测定将确定 Fas表达是功能性的。 Fas的lpr突变体形式的作用 将在照射前后检查细胞中p53水平， lpr小鼠，因为p53是辐射诱导的细胞凋亡的关键介质。 将确定除γ之外的细胞损伤机制是否存在 辐射，如热休克和紫外线照射涉及Fas/Fas L系统。 这些实验将明确Fas/Fas L在组织中的作用， 可能有助于阐明其在系统性自身免疫中的作用。

Lpr and gld mice have phenotypic and functional abnormalities resembling human SLE due to abnormal Fas and Fas ligand (Fas L) apoptosis genes, respectively. Apoptosis is a form of programmed cell death and is necessary for the elimination of self-reactive lymphocytes from the immune system. The surprising finding that Fas is involved in radiation- induced apoptosis suggests a new role for the Fas/Fas L system in deleting cells following environmental trauma. This proposal will define the role of Fas/Fas L in apoptosis after gamma irradiation using a short term in vitro culture system. The regulation of Fas expression on injured cells of normal and lpr mice will be studied by examining Fas expression and transcription after irradiation. In vivo short term chimera experiments and in vivo cytotoxicity assays will determine if the Fas expressed is functional. The effect of the lpr mutant form of Fas on p53 levels will be examined before and after irradiation in cells from lpr mice, since p53 is a key mediator of radiation-induced apoptosis. It will be determined if mechanisms of cell injury other than gamma irradiation, such as heat shock and UV irradiation involve the Fas/Fas L system. These experiments will define the role of Fas/Fas L in tissue injury and may help clarify its role in systemic autoimmunity.