Role of HMGB1 in Bacterial Keratitis

描述(申请人提供)：铜绿假单胞菌是一种常见的机会致病菌，可导致细菌性角膜炎，尤其是在使用隐形眼镜时(每年25,000-30,000例，治疗费用估计为1,500-3,000万美元)。这些研究的目的是确定细菌性角膜炎的发生机制，特别是高迁移率族蛋白1(HMGB1)的作用，HMGB1是典型的警报蛋白。HMGB1是危险相关分子模式(DAMP)家族的成员之一，是全身炎症反应综合征的介质，在细菌感染/脓毒症晚期升高，被认为是疾病治疗的靶点。鉴于其在天然免疫中的重要性，根据细胞定位具有不同的功能，并具有与Toll样受体(TLR)和其他分子如晚期糖基化终产物受体(RAGE)结合的能力，我们推测并提供了初步的支持数据，即它对角膜炎症细胞反应具有显著的放大作用，是铜绿假单胞菌角膜炎的重要治疗靶点。这次竞争性更新中描述的实验是目前资助的TLR4研究的一个合乎逻辑的片段，因为我们将重点放在HMGB1上，HMGB1是一种与TLR配体和细胞因子相互作用的分子，并通过包括TLR2、4和RAGE在内的多种表面受体激活细胞。虽然HMGB1是一个研究得很好的湿疹家族的成员，但目前还没有关于它在感染的角膜中所起作用的信息。因此，HMGB1如何在铜绿假单胞菌角膜感染中发挥作用，放大宿主免疫反应，并成为治疗的靶点，将被确定。提出了两个目标。具体目标1：将验证HMGB1放大角膜炎症并调节细菌性角膜炎驻留细胞和浸润性细胞的效应功能的假设。具体目标2：将检验HMGB1是一种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相关，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.