TGF BETA--INDUCED APOPTOSIS IN B LYMPHOCYTES

转化生长因子β(TGFβ)是一类典型的 具有免疫调节特性的细胞因子对 维持正常的免疫平衡。有针对性地破坏 小鼠的TGFbeta基因导致一种表型，其特征是 自身免疫典型的进行性多灶性炎症过程 循环自身抗体和免疫复合体增加的疾病 沉积，两类MHC抗原表达增加，以及 循环中未成熟的中性粒细胞和淋巴细胞数量增加。 转化生长因子β基因敲除中的炎症反应是由淋巴细胞介导的 论证转化生长因子β在调节淋巴细胞中的重要作用 扩散和激活，这有助于维持 自我宽容。在这个提案中，我们希望确定分子 转化生长因子β诱导未成熟B细胞凋亡的机制 导致克隆性缺失和自我耐受性的维持。我们 假设有不同的胞内结构域 介导细胞凋亡的同型和/或异型转化生长因子β受体复合体 在WEHI-231B淋巴细胞中。我们还建议，一个独特的和 此前未知的半胱氨酸蛋白酶(S)负责介导 转化生长因子β的促凋亡作用。这是本应用程序的目标 确定转化生长因子β受体复合体的类型和细胞内 该复合体在转化生长因子β诱导的细胞凋亡中所必需的区域 WEHI-231细胞。我们还建议分离和鉴定caspase。 这些细胞中由转化生长因子β激活的蛋白水解酶(S)。

Transforming growth factor beta (TGFbeta) is prototypic of a family of cytokines with immunoregulatory properties that are critical to the maintenance of normal immunological homeostasis. Targeted disruption of the TGFbeta gene in mice results in a phenotype characterized as a progressive multifocal inflammatory process typical of autoimmune disease with increased circulating autoantibodies and immune complex deposition, increased expression of both classes of MHC antigens, and increased numbers of circulating immature neutrophils and lymphocytes. The inflammatory response in the TGFbeta-knockout is lymphocyte mediated demonstrating the vital role of TGFbeta in regulating lymphocyte proliferation and activation, which contribute to the maintenance of self tolerance. In this proposal we wish to determine the molecular mechanism by which TGFbeta induces apoptosis in immature B cells thus resulting in clonal deletion and maintenance of self tolerance. We hypothesize that there are distinct intracellular domains of either a homo and/or heteromeric TGFbeta receptor complex which mediate apoptosis in the WEHI-231 B lymphocyte cells. We also propose that a distinct and previously unidentified caspase protease(s) is responsible for mediating the apoptotic actions of TGFbeta. It is the goal of this application to determine the type of TGFbeta-receptor complex and the intracellular regions of this complex necessary for TGFbeta-induced apoptosis in WEHI-231 cells. We also propose to isolate and characterize the caspase protease(s) which is activated by TGFbeta in these cells.