Positive and negative regulation of TNF alpha signaling

描述(由申请人提供)：关节炎是一种影响4300万美国人的疾病。关节炎的病因通常是未知的。然而，炎症和免疫反应的失调显然在这些疾病中起着非常重要的作用，因为许多类型的关节炎涉及不同器官的慢性炎症。肿瘤坏死因子α(TNFpha)是一种促炎细胞因子，在类风湿关节炎的炎症过程中发挥重要作用。尽管肿瘤坏死因子α是调节正常炎症和免疫反应所必需的，但在细菌感染期间，急性升高的肿瘤坏死因子α水平可能会导致感染性休克，而长期升高的肿瘤坏死因子α水平与类风湿关节炎的炎症过程有关。肿瘤坏死因子α水平升高可诱导多种炎症基因的表达。这些基因的表达被认为会导致类风湿性关节炎的肿胀、疼痛和其他影响。体外和体内对肿瘤坏死因子α功能的抑制已经被证明影响到几种炎症的动物模型。调节肿瘤坏死因子α水平也被证明可以减少严重活动期类风湿性关节炎患者的体征和症状。因此，了解肿瘤坏死因子α功能的分子机制将为关节炎疾病的治疗提供更多的治疗途径。本提案旨在应用分子工具来阐明导致核因子-kB激活的确切的TNFpha信号通路，核因子-kB是控制各种炎症基因表达的主要转录因子。具体地说，我们将研究RIP是如何传递TNFpha信号来激活NF-kB的，RIP是TNFpha途径中的一个关键信号中间体。我们还将研究肿瘤坏死因子α诱导的信号通路是如何负调控的。最后，我们将使用遗传互补方法来确定TNFpha诱导的NF-kB激活所需的未知信号成分。这些研究将提供关于TNFpha信号被传递到下游组件的分子机制的重要新信息，这些下游组件激活控制炎症基因表达的核因子-kB家族。

DESCRIPTION (provided by the applicant): Arthritis is a class of disease that affects 43 million Americans. The causes of arthritis are, in general, unknown. However, dysregulated inflammatory and immune responses apparently play very important roles in these diseases, since many types of arthritis involve chronic inflammation in different organs. Tumor necrosis factor alpha (TNFalpha) is a pro-inflammatory cytokine and plays an important role in the inflammatory processes of rheumatoid arthritis. Although TNFalpha is required for regulation of normal inflammatory and immune responses, acute elevated levels of TNFalpha may lead to septic shock during bacterial infection, while chronically elevated levels of TNFalpha are associated with the inflammatory processes of rheumatoid arthritis. Elevated levels of TNFalpha induce expression of many inflammatory genes. Expression of these genes is thought to elicit the swelling, pain and other effects of rheumatoid arthritis. Inhibition of TNFalpha function in vitro and in vivo has been shown to affect several animal models of inflammation. Modulation of TNFalpha levels has also been shown to reduce signs and symptoms of severely active rheumatoid arthritis patients. Thus, understanding the molecular mechanism of TNFalpha function will provide more therapeutic approaches for treatment of arthritic diseases. The present proposal seeks to apply molecular tools to elucidate the precise TNFalpha signaling pathway that leads to activation of NF-kB, a major transcription factor that controls the expression of various inflammatory genes. Specifically, we will investigate how RIP, a key signaling intermediate in the TNFalpha pathway, transmits TNFalpha signals to activate NF-kB. We will also examine how TNFalpha -induced signaling pathway is negatively regulated. Finally, we will use genetic complementation approaches to identify unknown signaling components that are required for TNFalpha -induced NF-kB activation. These studies will provide essential new information about the molecular mechanisms by which TNFalpha signals are transmitted to downstream components that activate the NF-kB family of transcription factors controlling expression of inflammatory genes.