Role of GSK3 in host inflammation

描述（由申请人提供）：本项目的总体目标是阐明相互作用的内源性抗炎途径，这些途径可用于抑制宿主对牙周细菌和其他病原体的过度旺盛反应。细菌最初由Toll样受体（TLR）和先天细胞上表达的其他病原体识别受体识别。TLR与微生物特异性分子模式的相互作用诱导促炎细胞因子的先天产生，其引导免疫应答的强度和方向，导致白细胞募集到感染部位，并产生大量抗菌分子，其中许多具有引起限定破坏性炎性疾病的附带组织损伤的潜力。至少有三种内源性抗炎途径。DE 017680的第一个生命周期集中于体外阐明PI 3 K/ AKT抗炎途径、GSK 3b在该信号级联中的关键作用以及该途径除了控制T细胞发育和增殖之外还调节固有细胞中IFNb、IL-lRa、IL-10表达的机制。除了PI 3 K/ AKT级联之外，该更新还将考虑α 7烟碱乙酰胆碱受体依赖性胆碱能和Wnt 3a抗炎途径。这三种途径之间的串扰将被阐明，特别注意中枢炎症介质，GSK 3b，在途径收敛的关键作用。虽然每种途径本身都是有效的，但最大化会聚信号事件的抗炎潜力的治疗干预可能特别有效。为此，将使用炎症（皮下腔）和牙周炎（牙槽骨损失）的鼠模型来开发抗炎信号传导事件。因此，该项目将为开发治疗牙周炎和其他炎症性疾病的新方法奠定基础，并确定应易于翻译的治疗靶点。

DESCRIPTION (provided by applicant): The overall goal of this project is to elucidate interacting endogenous anti-inflammatory pathways that can be harnessed to suppress an over-exuberant host response to periodontal bacteria and other pathogens. Bacteria are initially recognized by Toll-like receptors (TLRs) and other pathogen recognition receptors expressed on innate cells. TLR interaction with microbe-specific molecular patterns induces the innate production of pro- inflammatory cytokines, which direct the intensity and direction of the immune response, leads to recruitment of leukocytes to the site of infection, and the production of an arsenal of anti-bacterial molecules, many of which have the potential to cause the collateral tissue damage that defines destructive inflammatory diseases. There are at least three endogenous anti-inflammatory pathways. The first life cycle of DE017680 focused on the in vitro elucidation of the PI3K/ AKT anti-inflammatory pathway, the key role of GSK3b in this signaling cascade, and the mechanisms by which this pathway regulates the expression of IFNb, IL-1Ra, IL-10 in innate cells in addition to controlling T cell development and proliferation. In addition o the PI3K/ AKT cascade, this renewal will also consider the a7 nicotinic acetylcholine receptor-dependent cholinergic and the Wnt3a anti- inflammatory pathways. Crosstalk between these three pathways will be elucidated, with particular attention paid to the pivotal role of the centra inflammatory mediator, GSK3b, in pathway convergence. While each pathway is efficacious in its own right, therapeutic interventions that maximize the anti-inflammatory potential of convergent signaling events are likely to be particularly potent. To this end, anti-inflammatory signaling events will be exploited using murine models of inflammation (sub-cutaneous chamber) and periodontitis (alveolar bone loss). Therefore, this project will lay the groundwork for the development of novel approaches to the treatment of periodontitis and other inflammatory diseases and identify therapeutic targets that should be readily translatable.