Role of GSK3 in host inflammation

GSK3 在宿主炎症中的作用

• 批准号: 8627598
• 负责人: David A Scott
• 金额: $ 37.5万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-04-25 至 2018-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8627598
• 关键词: Alveolar Bone Loss; Amplifiers; Anti-Bacterial Agents; Anti-Inflammatory Agents; Anti-inflammatory; Attention; Bacteria; Bacterial Infections; Cardiovascular system; Cells; Cessation of life; Chronic; Communicable Diseases; Complex; Cutaneous; Data; Dental Plaque; Development; Disease; Disease Progression; Event; Glycogen Synthase Kinases; Goals; Health Care Costs; Host Defense; Human; Immune; Immune response; Immune system; In Vitro; Infection; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Interferon-beta; Interleukin-10; Invaded; Lead; Leukocytes; Life Cycle Stages; Lung diseases; Matrix Metalloproteinases; Mediating; Microbe; Modeling; Molecular; Mus; Natural Immunity; Nature; Nicotinic Receptors; PI3K/AKT; Pathology; Pathway interactions; Pattern; Pattern recognition receptor; Periodontal Diseases; Periodontitis; Pharmacologic Substance; Play; Porphyromonas gingivalis; Production; Regulation; Role; Seminal; Signal Pathway; Signal Transduction; Site; T-Cell Development; TLR2 gene; TLR4 gene; Testing; Therapeutic; Therapeutic Intervention; Tissues; Toll-like receptors; anakinra; cholinergic; controlled release; cytokine; driving force; in vivo; microbial; novel; novel strategies; oral pathogen; pathogen; pathogenic bacteria; public health relevance; receptor; response; therapeutic target; tool

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.

描述（由申请人提供）：该项目的总体目标是阐明可以利用的相互作用的内源性抗炎途径，以抑制对牙周细菌和其他病原体的过度过度宿主反应。细菌最初是通过Toll样受体（TLR）和其他在先天细胞表达的病原体识别受体识别的。 TLR与微生物特异性分子模式的相互作用引起了炎性细胞因子的先天产生，该细胞因子指导免疫反应的强度和方向，从而导致白血病细胞募集到感染部位，并导致抗细菌的抗细菌症的产生分子，其中许多有可能引起定义破坏性炎症性疾病的附带组织损害。至少有三种内源性抗炎途径。 DE017680的第一个生命周期集中于PI3K/ AKT抗炎途径的体外阐明，GSK3B在此信号级联中的关键作用以及该途径调节IFNB的表达的机制除了控制T细胞的发育和增殖外，先天细胞中的-10。另外，在PI3K/ AKT级联反应中，该更新还将考虑A7烟碱乙酰胆碱受体依赖性胆碱能和WNT3A抗炎症途径。将阐明这三个途径之间的串扰，特别注意中心炎症介体GSK3B在途径收敛中的关键作用。尽管每条途径本身都是有效的，但最大化收敛信号事件的抗炎潜力的治疗干预措施可能特别有效。为此，将使用炎症的鼠模型（皮下腔室）和牙周炎（肺泡骨质流失）来利用抗炎信号事件。因此，该项目将为开发牙周炎和其他炎症性疾病的新方法开发奠定基础，并确定应易于翻译的治疗靶标。