TGF BETA--INDUCED APOPTOSIS IN B LYMPHOCYTES

转化生长因子β（TGF β）是一个家族的原型， 具有免疫调节特性的细胞因子， 维持正常的免疫稳态。靶向破坏 小鼠中的TGF β基因导致一种表型， 进行性多灶性炎症过程，典型的自身免疫性 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。 TGF β基因敲除的炎症反应是淋巴细胞介导的， 证明了TGF β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 在这个建议中，我们希望确定分子 TGF β诱导未成熟B细胞凋亡的机制 导致克隆缺失和自身耐受性的维持。 我们 假设存在不同的细胞内结构域， 介导细胞凋亡同源和/或异源TGF β受体复合物 在WEHI-231 B淋巴细胞中。 我们还建议， 以前未鉴定的半胱天冬酶蛋白酶负责介导 TGF β的凋亡作用。 这是这个应用程序的目标 以确定TGF β-受体复合物的类型和细胞内的 TGF β诱导的细胞凋亡所必需的复合物区域， WEHI-231细胞。 我们还建议分离和表征caspase 蛋白酶，其在这些细胞中被TGF β激活。

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.