CD40 SIGNALING THROUGH TNF RECEPTOR ASSOCIATED FACTORS

通过 TNF 受体相关因子进行 CD40 信号传导

• 批准号: 6351247
• 负责人: GENHONG CHENG
• 金额: $ 40.92万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-02-01 至 2004-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6351247
• 关键词: CD40 molecule; biological signal transduction; cytokine; flow cytometry; gel mobility shift assay; gene expression; growth factor receptors; immunoprecipitation; northern blottings; nuclear factor kappa beta; oligonucleotides; polymerase chain reaction; protein kinase; protein purification; protein structure function; receptor binding; site directed mutagenesis; tissue /cell culture; tumor necrosis factor alpha; western blottings; yeast two hybrid system

Tumor necrosis factor (TNF) has been considered as an anti-cancer agent since its discovery two decades ago. Members of the TNF receptor (TNFR) superfamily can send both survival and death signals to cells, and play important roles in a wide range of biological effects that include acute phase responses and lymphocyte activation. CD40, as a member of this receptor family, activates multiple signaling pathways, induces expression of dozens of genes, and is essential for many important events in T-cell-dependent humoral responses. Our goal is to find connections that can link the CD40 receptor to multiple signal transduction pathways, and that link each signaling pathway to its downstream effector genes and to the CD40-mediated biological functions. The recent discovery of several early signaling mediators, including the TNF receptor-associated factor (TRAF) family proteins, the TRAF- associated NF-kappaB activator (TANK) and the NF-kappaB-inducing kinase (NIK), has provided an opportunity to dissect multiple CD40-mediated signal transduction pathways. This proposal will focus on the early events of CD40 receptor-initiated signaling. First, we will determine the specificities of multiple TRAF proteins for receiving signals from CD40 and for sending out downstream signals to activate both the NF-kappaB and stress-activating protein kinase (SAPK) signal transduction pathways. Second, we will determine the molecular mechanisms of TRAF and TANK cooperation. We will also test the possible role of TANK as a switching molecule in controlling the threshold of CD40-induced NF-KB and SAPK activation. Our work will: 1) provide new insights into the molecular mechanisms by which a single receptor interacting with its ligand can generate multiple signal transduction pathways and control multiple biological events; and 2) identify new therapeutic targets in the multiple CD40 and TNF signaling pathways for treatment of cancers and immune diseases.

肿瘤坏死因子（TNF）已被认为是一种抗癌剂 自从二十年前发现以来。 TNF 受体 (TNFR) 的成员 超家族可以向细胞发送生存和死亡信号，并发挥作用 在广泛的生物效应中发挥重要作用，包括急性 相反应和淋巴细胞激活。 CD40，作为该组织的成员 受体家族，激活多种信号通路，诱导 数十种基因的表达，对于许多重要的基因至关重要 T 细胞依赖性体液反应中的事件。 我们的目标是找到 可以将 CD40 受体与多个信号连接的连接 转导途径，并将每个信号传导途径与其 下游效应基因和 CD40 介导的生物学功能。 最近发现了几种早期信号传导介质，包括 TNF 受体相关因子 (TRAF) 家族蛋白，TRAF- 相关 NF-kappaB 激活剂 (TANK) 和 NF-kappaB 诱导激酶 （NIK），提供了一个机会来剖析多个 CD40 介导的 信号转导途径。 该提案将重点关注 CD40 受体引发的早期事件 发信号。 首先，我们将确定多个TRAF的特殊性 用于接收来自 CD40 的信号并向下游发送信号的蛋白质 激活 NF-κB 和应激激活蛋白的信号 激酶 (SAPK) 信号转导途径。其次，我们将确定 TRAF和TANK合作的分子机制。 我们还将 测试 TANK 作为开关分子在控制中的可能作用 CD40 诱导的 NF-KB 和 SAPK 激活阈值。 我们的工作将：1）通过以下方式提供对分子机制的新见解 单个受体与其配体相互作用可以产生 多种信号转导途径，控制多种生物 事件； 2) 确定多种 CD40 和 用于治疗癌症和免疫疾病的 TNF 信号通路。