ROLE OF BCAP IN REGULATING INFLAMMATION AND ADAPTIVE IMMUNITY

 描述（由申请人提供）：Toll样受体（TLR）识别在多种病原体（包括细菌、病毒和原生动物）上表达的保守微生物结构。TLR的激活导致诱导炎症反应，这有助于先天免疫系统的细胞消除病原体，但也可能导致组织损伤和炎性疾病。在配体识别后，TLR使用其称为Toll-IL-1受体同源结构域（TIR结构域）的胞质结构域将信号传递到细胞中。所有已知的TLR信号传导衔接子如Myd 88、TIRAP、TRIF和TRAM具有C-末端TIR结构域，它们用于与TLR的TIR结构域相互作用并通过激活转录因子如NF-B、AP-1和IRF蛋白诱导促炎细胞因子产生。我们最近发现了一种新的TLR信号转导适配器，称为BCAP，它也具有TIR结构域并参与TLR信号转导途径。BCAP的重要性在于将TLR与PI 3激酶激活联系起来至关重要。PI 3激酶调节细胞行为的几种结果，例如细胞增殖和细胞存活。此外，我们还发现BCAP在调节炎症反应中的重要性，至少部分是由于其激活PI 3激酶的能力。我们的初步研究已经确定BCAP在调节巨噬细胞行为和功能中起重要作用，并且对于炎症损伤后的伤口愈合和组织修复至关重要。此外，我们还发现BCAP在调节IL-1和IL-18受体下游信号传导中起重要作用。这两种细胞因子受体也使用TIR结构域进行信号传导，MyD 88是IL-1受体家族下游的已知信号传导衔接子。我们的数据表明，BCAP在T细胞中的IL-1受体家族下游也起着关键作用，并且对于调节Th 1和Th 17细胞分化很重要。我们的总体目标是阐明BCAP在炎症过程中调节体内巨噬细胞功能的机制，并了解BCAP在调节适应性免疫中的作用。我们提出了两个主要目标：Aim 1将了解BCAP在调节巨噬细胞基因表达中的作用以及BCAP调节炎症的分子机制。Aim 2将研究BCAP在调节树突状细胞功能中的作用，以及BCAP在IL-1和IL-18受体信号传导中的作用及其对T细胞活化和分化的影响。这些研究对于了解TLR/IL-1 R受体超家族下游BCAP和PI 3 K活化的作用及其在免疫应答和炎症调节中的重要性至关重要。

 DESCRIPTION (provided by applicant): Toll-like receptors (TLRs) recognize conserved microbial structures expressed on a wide variety of pathogens including bacteria, viruses and protozoa. Activation of TLRs leads to induction of inflammatory responses that helps cells of the innate immune system to eliminate the pathogen but can also cause tissue damage and inflammatory diseases. After ligand recognition, TLRs transmit signals into the cell using their cytoplasmic domain called Toll-IL-1 receptor homology domain (TIR domain). All known TLR signaling adapters such as Myd88, TIRAP, TRIF and TRAM have C-terminal TIR domains that they use for interact with TIR domains of TLRs and induce pro-inflammatory cytokine production through activation of transcription factors such as NF-¿B, AP-1 and IRF proteins. We have recently identified a new TLR signaling adapter called BCAP that also has a TIR domain and participates in the TLR signaling pathway. The importance of BCAP is that it is critical to link TLRs to PI3 Kinase activation. PI3 Kinase regulates several outcomes of cellular behavior such as cell proliferation and cell survival. In addition we also find that BCAP is important to regulat inflammatory responses at least in part due to its ability to activate PI3 Kinase. Our preliminary studies have identified that BCAP plays an important role in regulating macrophage behavior and function and is critical for would healing and tissue repair following inflammatory damage. In addition we have also discovered that BCAP plays an essential role in regulating signaling downstream of IL-1 and IL-18 receptors. These two cytokine receptors also use TIR domains to signal and MyD88 is a known signaling adapter downstream of IL-1 family of receptors. Our data suggest that BCAP also plays a critical role downstream of IL-1 family of receptors in T cells and is important for regulating Th1 and Th17 cell differentiation. Our overall goals of this proposal are to elucidate the mechanisms by which BCAP regulates macrophage function in vivo during inflammation and also to understand the role of BCAP in regulating adaptive immunity. We propose two major aims in this proposal: Aim1 will understand the role of BCAP in regulating gene expression in macrophages and the molecular mechanisms by which BCAP regulates inflammation. Aim2 will investigate the role of BCAP in regulating dendritic cell function as well as the role of BCAP in IL-1 and IL-18 receptor signaling and its influence on T cell activation and differentiation. These studies will be critical to understand the role of BCAP and PI3K activation downstream of TLR/IL-1R super family of receptors and its importance in regulation of immune responses and inflammation.