Role of GSK3 in host inflammation

描述（由申请人提供）：这个项目的总体目标是阐明相互作用的内源性抗炎途径，可以用来抑制宿主对牙周细菌和其他病原体的过度反应。细菌最初由toll样受体（TLRs）和其他病原体识别受体在先天细胞上表达。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，促炎细胞因子指导免疫反应的强度和方向，导致白细胞聚集到感染部位，并产生一系列抗菌分子，其中许多抗菌分子有可能导致附带组织损伤，从而定义破坏性炎症性疾病。至少有三种内源性抗炎途径。DE017680的第一个生命周期集中在体外阐明PI3K/ AKT抗炎通路，GSK3b在该信号级联中的关键作用，以及该通路除了控制T细胞的发育和增殖外，调节先天细胞中IFNb， IL-1Ra， IL-10的表达的机制。除了PI3K/ AKT级联外，这种更新还将考虑a7烟碱乙酰胆碱受体依赖性胆碱能和Wnt3a抗炎途径。这三条通路之间的相互作用将被阐明，并特别关注中央炎症介质GSK3b在通路收敛中的关键作用。虽然每一种途径都是有效的，但最大限度地发挥趋同信号事件的抗炎潜力的治疗干预可能特别有效。为此，将利用小鼠炎症（皮下腔）和牙周炎（牙槽骨丢失）模型来研究抗炎信号事件。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.