Cytokine Signaling

描述（由申请人提供）：I型干扰素（ifn）是抵御病毒感染的第一道防线，在调节细胞增殖中发挥重要作用。这两种作用都需要激活Jak-STAT通路，然而，ifn激活其他通路，也干预其抗病毒和抗增殖功能。I型ifn的生长抑制作用机制尚不完全清楚。此外，根据不同的环境，ifn可以具有细胞抑制作用，诱导细胞凋亡，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。我们克隆了一个叫做BARA的基因。BARA与I型干扰素受体的β - al链相互作用。在秀丽隐杆线虫中，BARA的同系物是Cyclin d - cdk4 -视网膜母细胞瘤（RB）通路（称为通路B）的一部分，该通路与另一个冗余通路（称为通路A）一起负性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ifn细胞生长抑制作用的作用。

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.