Role of HMGB1 in Bacterial Keratitis

项目总结/摘要 铜绿假单胞菌（P. aeurginosa）是一种常见的条件致病菌， 角膜炎，尤其是在接触透镜使用中（每年25，000 - 30，000例，治疗费用估计为15 -30美元 百万）。拟议研究的目标是确定细菌发育所涉及的机制 角膜炎，特别是高迁移率族蛋白1（HMGB 1）的作用，原型报警。HMGB 1是一个成员 危险相关分子模式（DAMPS）家族，全身炎症介质， 在细菌感染/脓毒症后期升高，并被认为是疾病治疗的靶点。 鉴于它在先天免疫中很重要，具有依赖于细胞定位的不同功能，并且具有 结合Toll样受体（TLR）和其它分子如晚期糖基化末端受体能力 我们假设并提供了初步的支持性数据，即它具有显着的放大作用， 对角膜炎性细胞反应有影响，是铜绿假单胞菌的重要治疗靶点 角膜炎。在这个竞争性的更新描述的实验是一个合乎逻辑的segue从目前资助的 研究TLR 4，因为我们将集中在HMGB 1，一种与TLR配体和细胞因子相互作用的分子， 通过多种表面受体激活细胞，包括TLR 2，4和TLR 3。虽然HMGB 1是一个很好的- 作为DAMPS家族的成员，没有关于其在感染角膜中作用的信息。因此如何 HMGB 1可以设置阶段，放大宿主免疫应答，并且是治疗的靶点，将被确定 绿脓杆菌角膜感染提出了两个目标。具体目标1：将检验以下假设： HMGB 1放大角膜炎症并调节角膜上皮细胞中常驻细胞和浸润细胞的效应功能 细菌性角膜炎具体目标2：将检验HMGB 1是一种新的治疗靶点的假设， 临床相关性。这项工作与人类健康有关，具有相当大的医学和经济价值。 冲击

Project Summary/Abstract Pseudomonas aeruginosa (P. aeurginosa) is a common opportunistic pathogen which causes bacterial keratitis, especially in contact lens usage (25,000-30,000 cases annually with treatment estimated at $15-30 million). The goal of the studies proposed is to determine the mechanisms involved in development of bacterial keratitis, especially the role of high mobility group box 1 (HMGB1), a prototypic alarmin. HMGB1 is a member of a family of danger associated molecular patterns (DAMPS), a mediator of the systemic inflammatory response syndrome, is elevated late in bacterial infection/sepsis and considered a target for disease treatment. Given that it is important in innate immunity, has different functions dependent on cellular localization, and has the ability to bind to Toll-like-receptors (TLR) and other molecules such as receptor for advanced glycation end products (RAGE), we hypothesize and provide preliminary supportive data, that it has significant amplification effects on the corneal inflammatory cell response and is an important therapeutic target in P. aeruginosa keratitis. Experiments described in this competitive renewal are a logical segue from the currently funded studies on TLR4, as we will focus on HMGB1, a molecule which interacts with TLR ligands and cytokines and activates cells through multiple surface receptors including TLR2, 4 and RAGE. Although HMGB1 is a well- studied member of a family of DAMPS, no information on its role in the infected cornea is available. Thus, how HMGB1 may set the stage, amplify the host immune response and is a target for treatment, will be determined in P. aeruginosa corneal infection. Two aims are proposed. Specific Aim 1: Will test the hypothesis that HMGB1 amplifies corneal inflammation and modulates the effector function of resident and infiltrating cells in bacterial keratitis. Specific Aim 2: Will test the hypothesis that HMGB1 is a novel target for treatment and has clinical relevancy. The work is of relevance to human health and has considerable medical and economic impact.