ROLE OF BCAP IN REGULATING INFLAMMATION AND ADAPTIVE IMMUNITY

BCAP 在调节炎症和适应性免疫中的作用

• 批准号: 9782021
• 负责人: Chandrashekhar Pasare
• 金额: $ 15.29万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-14 至 2020-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9782021
• 关键词: ROLE; BCAP; REGULATING; INFLAMMATION; ADAPTIVE

 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.

 描述(申请人提供)：Toll样受体(TLRs)识别在包括细菌、病毒和原生动物在内的各种病原体上表达的保守微生物结构。TLRs的激活会导致炎症反应的诱导，这有助于先天性免疫系统的细胞消除病原体，但也会导致组织损伤和炎症性疾病。在配体识别后，TLRs利用其胞浆结构域Toll-IL-1受体同源结构域(TIR结构域)将信号传递到细胞内。所有已知的TLR信号转接子，如MyD88、TIRAP、TRIF和TRAM都含有C-末端的TIR结构域，它们用来与TLR的TIR结构域相互作用，并通过激活转录因子如核因子-βB、AP-1和IRF蛋白来诱导促炎细胞因子的产生。我们最近发现了一种新的TLR信号转接子，称为BCAP，它也具有TIR结构域，并参与TLR信号通路。BCAP的重要性在于，将TLRs与PI3激酶激活联系起来是至关重要的。PI3Kinase调节细胞行为的几个结果，如细胞增殖和细胞存活。此外，我们还发现，BCAP对调节炎症反应很重要，至少部分是因为它能够激活PI3Kinase。我们的初步研究证实，BCAP在调节巨噬细胞的行为和功能方面发挥着重要作用，对于炎症损伤后的WE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受体下游的信号通路中起着重要作用。这两种细胞因子受体也使用TIR结构域来传递信号，而MyD88是IL-1受体家族下游的已知信号转接子。我们的数据表明，BCAP也在T细胞中IL-1受体家族的下游发挥关键作用，并对调节Th1和Th17细胞的分化很重要。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在调节获得性免疫中的作用。我们在这项提议中提出了两个主要目标：AIM1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。AIM2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受体信号转导中的作用及其对T细胞激活和分化的影响。这些研究对于了解TLR/IL-1R超家族受体下游BCAP和PI3K的激活作用及其在免疫反应和炎症调节中的重要性至关重要。