TNFA RECEPTOR CD120A INDUCED SIGNALING IN MACROPHAGES

描述（根据申请人的摘要和具体目标改编）： 肿瘤坏死因子α（TNF α）与许多人类肿瘤相关。 疾病过程，特别是那些涉及肺的巨噬细胞 似乎是重要的靶细胞。 TNF α被细胞识别 表面受体CD 120 a（p55）和CD 120 b（p75）。 结扎和 CD 120 a（p55）的聚集是诱导细胞凋亡所必需的。 大多数细胞对TNFa的反应，包括一氧化氮的诱导 氧化物和巨噬细胞的胰岛素样生长因子-1表达。 已经报道了几种信号转导机制， 包括激酶级联反应， 介导p42 MAPK/ERK 2的激活。 目前尚不清楚这是如何 激酶级联与CD 120 a（p55）偶联。 它是假设 通过CD 120 a（p55）的信号传导由磷蛋白pp 95启动 和/或pp 120，其通过它们与 CD 120 a（p55）的胞内结构域，使细胞之间的通信， 受体和远端激酶信号级联通过RAS。 具体 目的是：1）纯化和克隆磷蛋白pp 95和pp 120， 与细胞内结构域（ICD）组成性相关的蛋白质 研究pp 95和pp 120在CD 120 a（p55）中的作用， 确定CD 120 a（p55）ICD内与CD 120 a（p55）相互作用的区域， 用pp 95和pp 120;和3）确定上游激酶， 负责激活p42 MAPK/ERK 2的信号传导组分。

DESCRIPTION (Adapted from the applicant's abstract and specific aims): Tumor necrosis factor alpha (TNFa) has been implicated in many human disease processes especially those involving the lung as macrophages appear to be important target cells. TNFa is recognized by the cell surface receptors CD120a, (p55) and CD120b (p75). Ligation and aggregation of CD120a (p55) are necessary for the induction of the majority of cellular responses to TNFa including the induction of nitric oxide and insulin-like growth factor-1 expression by macrophages. Several signal transduction mechanisms have been reported to be activated in response to activated TNFa including a kinase cascade that mediates the activation of p42mapk/erk2. It is not known how this kinase cascade is coupled to CD120a (p55). It is hypothesized that signalling through CD120a (p55) is initiated by the phosphoproteins pp95 and/or pp120 which, through their intrinsic association with the intracellular domain of CD120a (p55), enable communication between the receptor and the distal kinase signaling cascade via RAS. The specific aims are: 1) to purify and clone the phosphoproteins, pp95 and pp120, that are constitutively associated with the intracellular domain (ICD) of CD120a (p55); 2) to investigate the functions of pp95 and pp120 and to define the region(s) within the ICD of CD120a (p55) that interact with pp95 and pp120; and 3) to determine the upstream kinase(s) and signalling components responsible for activating p42mapk/erk2.