Positive and negative regulation of TNF alpha signaling

描述（由申请人提供）：关节炎是影响4300万美国人的一类疾病。一般来说，关节炎的病因尚不清楚。然而，失调的炎症和免疫反应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 (TNFalpha)是一种促炎细胞因子，在类风湿关节炎的炎症过程中起重要作用。虽然TNFalpha是正常炎症和免疫反应的调节所必需的，但在细菌感染期间，TNFalpha水平的急性升高可能导致感染性休克，而TNFalpha水平的长期升高与类风湿关节炎的炎症过程有关。高水平的TNFalpha诱导许多炎症基因的表达。这些基因的表达被认为引起了类风湿关节炎的肿胀、疼痛和其他影响。体外和体内TNFalpha功能的抑制已被证明影响几种动物炎症模型。TNFalpha水平的调节也被证明可以减少严重活动性类风湿关节炎患者的体征和症状。因此，了解TNFalpha功能的分子机制将为关节炎疾病的治疗提供更多的治疗方法。本研究旨在应用分子工具来阐明导致NF-kB激活的TNFalpha信号通路，NF-kB是控制各种炎症基因表达的主要转录因子。具体而言，我们将研究TNFalpha通路中的关键信号中间体RIP如何传递TNFalpha信号以激活NF-kB。我们还将研究TNFalpha诱导的信号通路如何受到负调控。最后，我们将使用遗传互补方法来鉴定TNFalpha诱导的NF-kB激活所需的未知信号成分。这些研究将为TNFalpha信号传递到下游组分的分子机制提供重要的新信息，这些下游组分激活了控制炎症基因表达的NF-kB转录因子家族。

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.