Cytokine Signaling

描述（由申请人提供）：I型干扰素（IFN）是抵抗病毒感染的第一道防线，在调节细胞增殖中发挥重要作用。这两种效应都需要激活Jak-STAT途径，然而，IFN激活其他途径也干预其抗病毒和抗增殖功能。I型干扰素的生长抑制作用的机制尚不完全清楚。此外，根据上下文，IFN可以具有细胞生长抑制作用，诱导凋亡，或者细胞可以完全抵抗。为了发现可能干预I型IFN生物学效应的新蛋白，我们使用IFN-R链作为诱饵进行了双杂交筛选。我们克隆了一个基因，叫做BARA。BARA与I型干扰素受体的β L链相互作用。BARA在C. elegans是细胞周期蛋白D-CDK 4-视网膜母细胞瘤（RB）途径（称为途径B）的一部分，其与另一冗余途径（称为途径A）一起负调节细胞周期进程和外阴发育。本项目将重点研究BARA对I型干扰素细胞生长抑制作用的影响。 在具体目标1中，我们将确定BARA在IFN诱导的生长抑制效应、凋亡和细胞衰老中的作用。 在具体目标2中，我们将检验IFN系统是哺乳动物等效于C中的途径（途径B）的假设。elegans负调控EGF-RAS-MAPK通路。 在特定目标3中，我们将确定BARA基因纯合缺失的小鼠是否具有IFN系统的改变。我们期望，要实现的目标，这一建议将阐明对I型干扰素的生长调节作用的理解。

DESCRIPTION (provided by applicant): Type I Interferons (IFNs) are the first line of defense against viral infections and play an important role in the regulation of cell proliferation. Both effects require the activation of the Jak-STAT pathway however, IFNs activate other pathways that also intervene in its antiviral and antiproliferative functions. The mechanism of the growth inhibitory action of type I IFNs is not completely clear. Moreover, depending on the context, IFNs can have either a cytostatic effect, induce apoptosis, or cells can be completely resistant. In order to discover new proteins that may intervene in the biological effects of type I IFNs, we performed a two-hybrid screening using the IFN-R chains as bait. We have cloned a gene termed BARA. BARA interacts with the betaL chain of the type I interferon receptor. The homolog of BARA in C. elegans is part of the Cyclin D-CDK4-retinoblastoma (RB) pathway (termed pathway B), which in conjunction with another redundant pathway (termed pathway A) negatively regulate cell cycle progression and vulval development. This project will focus on the role of BARA on the cell growth inhibitory effects of type I IFNs. In Specific Aim 1 we will determine the role of BARA in IFN-induced growth inhibitory effect, apoptosis and cell senescence. In Specific Aim 2 we will test the hypothesis that the IFN system is the mammalian equivalent to a pathway (pathways B) that in C. elegans negatively regulates EGF-RAS-MAPK pathway. In Specific Aims 3 we will determine if mice with a homozygous deletion of the BARA gene have alterations of the IFN system. We expect that the goals to be achieved with this proposal will shed light on the understanding of the growth regulatory effects of type I IFNs.