Role of HMGB1 in Bacterial Keratitis

描述（由申请方提供）：铜绿假单胞菌（铜绿假单胞菌）是一种常见的机会致病菌，可引起细菌性角膜炎，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1500 - 3000万美元）。提出的研究的目标是确定参与细菌性角膜炎发展的机制，特别是高迁移率族蛋白1（HMGB 1），一种原型报警蛋白的作用。HMGB 1是危险相关分子模式（DAMPS）家族的成员，是全身炎症反应综合征的介质，在细菌感染/脓毒症后期升高，并被认为是疾病治疗的靶点。考虑到它在先天免疫中很重要，具有依赖于细胞定位的不同功能，并且能够结合Toll样受体（TLR）和其他分子，如晚期糖基化终产物受体（EGFR），我们假设并提供初步的支持性数据，它对角膜炎性细胞反应具有显著的放大作用，是铜绿假单胞菌的重要治疗靶点角膜炎。在这种竞争性更新中描述的实验是目前资助的TLR 4研究的逻辑延续，因为我们将专注于HMGB 1，一种与TLR配体和细胞因子相互作用并通过多种表面受体（包括TLR 2，4和TLR 4）激活细胞的分子。虽然HMGB 1是DAMPS家族的一个成员，但没有关于其在感染的角膜中的作用的信息。因此，如何HMGB 1可以设置阶段，放大宿主免疫反应，并作为治疗的目标，将在铜绿假单胞菌角膜感染中确定。提出了两个目标。具体目标1：将测试HMGB 1放大角膜炎症并调节细菌性角膜炎中驻留细胞和浸润细胞的效应功能的假设。具体目标2：验证HMGB 1是一个新的治疗靶点并具有临床相关性的假设。这项工作与人类健康有关，并具有相当大的医疗和经济影响。

DESCRIPTION (provided by applicant): 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 hypothesisthat 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.