Role of TRAF1 in signaling by TNFR2 family members

描述（由申请人提供）：肿瘤坏死因子（TNF）及其同系物在广泛的生物过程中发挥重要作用，包括急性期反应、细胞生长和凋亡、炎症和淋巴细胞活化。TNF有两种受体：TNFR 1和TNFR 2。TNFR 2是一个跨膜蛋白家族，具有胞内区域，缺乏死亡结构域。TNFR 2家族受体中的每一种可与一种或几种TRAF信号转导分子缔合。TRAF 2、TRAF 3、TRAF 5和TRAF 6参与NF-κ B和AP-1转录因子的信号转导和激活。关于TRAF 1的功能知之甚少，除了它主要在活化的淋巴细胞中表达，并且与TNFR家族的许多不同成员相关，包括TNFR 2、CD 27、CD 30、4-1BB、OX-40、HVEM、TRANCE-R、XEDAR、AITR等。TRAF 1还与EB病毒（EBV）的潜伏膜蛋白1（LMP 1）结合。为了阐明TRAF 1的功能，我们产生了TRAF 1缺陷小鼠。与野生型T细胞相比，TRAF 1缺陷型T细胞对抗CD 3刺激表现出显著增加的增殖。来自TRAF 1缺陷小鼠的活化T细胞，而不是来自其正常同窝出生的小鼠的活化T细胞，通过增殖和激活NF-κ B和AP-1对TNF作出反应。此外，TRAF 1缺陷小鼠的皮肤对TNF诱导的T细胞介导的坏死过敏。总之，这些发现表明TRAF 1是TNF信号传导的负调节剂。我们建议应用最先进的知识和技术，以进一步了解TRAF 1在T和B淋巴细胞中的功能。我们计划解决三个重要问题： 1. TRAF 1负调控TNFR 2信号传导的确切生化机制是什么？我们将研究TRAF 1抑制TNFR 2信号传导的分子机制。我们将确定TRAF 1在TNFR 2信号转导中的作用，在TNFR 1和TNFR 1的信号转导中的TNFR 2的情况下，在TNFR 2的情况下。为此，我们将TRAF 1缺陷小鼠与TNFR 1或TNFR2.2缺陷小鼠进行繁殖。TRAF 1可能与TNFR 2家族的其他成员（包括OX 40、4- 1bb、CD 30和CD 27）具有相似的功能。TRAF 1-/-小鼠与OX 40-/-小鼠相反，在过敏性哮喘模型中反应过度。我们建议在体外和体内确定TRAF 1在OX 40信号转导中的作用. TRAF 1在EBV LMP 1信号传导中的作用是什么？我们将分析TRAF 1在EBV LMP 1信号转导和B细胞中的作用。

DESCRIPTION (provided by applicant): Tumor Necrosis Factor (TNF) and it homologues play important roles in a wide array of biological processes including the acute phase response, cell growth and apoptosis, inflammation and lymphocyte activation. TNF has two receptors: TNFR1and TNFR2. TNFR2 represent a family of transmembrane proteins with intracellular region, which lack a death domain. Each of TNFR2 family receptors may associate with one or several TRAF signal transduction molecules. TRAF2, TRAF3, TRAF5, and TRAF6 were shown to participate in signal transduction and activation of NF-kappaB and AP-1 transcription factors. Little is known about TRAF1 function except it is predominantly expressed in activated lymphocytes and is associated with a number of distinct members of the TNFR family, including TNFR2, CD27, CD30, 4-1BB, OX-40, HVEM, TRANCE-R, XEDAR, AITR and others. TRAF1 also binds to latent membrane protein 1 (LMP1) of Epstein-Barr virus (EBV). To elucidate the function of TRAF 1 we have generated TRAF 1-deficient mice. Compared to wild type T cells, TRAF1-deficient T cells exhibit markedly increased proliferation to anti-CD3 stimulation. Activated T cells from TRAF1-deficient mice, but not from their normal littermates, responded to TNF by proliferation and activation of NF-kappaB and AP-1. Furthermore, skin from TRAF1-deficient mice was hypersensitive to TNF-induced T-cell mediated necrosis. Taken together, these findings suggest that TRAF1 is a negative regulator of TNF signaling. We propose to apply state of the art knowledge and techniques to further understand TRAF1 function in T and B lymphocytes. We plan to address three important questions: 1. What is the precise biochemical mechanism of TRAF1 negative regulation of TNFR2 signaling? We will study the molecular mechanism of inhibition of TNFR2 signaling by TRAF1. We will determine the role of TRAF1 in signal transduction by TNFR2 in the absence of TNFR1 and signal transduction by TNFR1 in the absence of TNFR2. For this purpose we will breed TRAF1-deficient mice with mice deficient in TNFR1 or TNFR2.2. TRAF1 might have similar function for other members of TNFR2 family expressed on T cells, including OX40, 4- 1bb, CD30, and CD27. Then again, TRAF1-/- mice, in opposite to OX40-/- mice, were hyperresponsive in a model of allergic asthma. We propose to determine the role of TRAF1 in OX40 signaling in vitro and in vivo.3. What is the role of TRAF1 in signaling by EBV LMP1? We will analyze the role of TRAF1 in EBV LMP1 signaling and B cell.