TGF BETA--INDUCED APOPTOSIS IN B LYMPHOCYTES

转化生长因子β (TGFbeta) 是一个家族的原型 具有免疫调节特性的细胞因子对免疫系统至关重要 维持正常的免疫稳态。有针对性的破坏 小鼠体内的 TGFbeta 基因产生的表型特征为 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物增加的疾病 沉积，增加两类 MHC 抗原的表达，以及 循环中未成熟中性粒细胞和淋巴细胞数量增加。 TGFbeta 敲除中的炎症反应是淋巴细胞介导的 证明 TGFbeta 在调节淋巴细胞中的重要作用 增殖和激活，这有助于维持 自我宽容。 在本提案中，我们希望确定分子 TGFbeta诱导未成熟B细胞凋亡的机制 导致克隆删除和自我耐受的维持。 我们 假设存在不同的细胞内结构域 介导细胞凋亡的同聚和/或异聚TGFbeta受体复合物 在 WEHI-231 B 淋巴细胞中。 我们还建议建立一个独特且 先前未识别的 caspase 蛋白酶负责介导 TGFbeta 的细胞凋亡作用。 这是这个应用程序的目标 确定 TGFβ 受体复合物的类型和细胞内 该复合物的区域是 TGFbeta 诱导细胞凋亡所必需的 WEHI-231 细胞。 我们还建议分离和表征半胱天冬酶 这些细胞中被 TGFbeta 激活的蛋白酶。

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.