Role of HMGB1 in Bacterial Keratitis

HMGB1 在细菌性角膜炎中的作用

基本信息

批准号：
8829266
负责人：
LINDA D HAZLETT
金额：
$ 37.24万
依托单位：
WAYNE STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-01-01 至 2017-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8829266
关键词：
Address Advanced Glycosylation End Products Amplifiers Anti-Inflammatory Agents Apoptosis Automobile Driving Autophagocytosis Bacterial Infections Binding Blindness Boxing C57BL/6 Mouse Caspase-1 Cells Clinical Clinical Treatment Contact Lenses Cornea Corneal Diseases Corneal Stroma Cytokine Network Pathway Data Dendritic Cells Dendritic cell activation Development Disease Effectiveness Epithelial Cells Extended-Wear Contact Lenses Family Funding Generations Genes Goals Grant Growth Factor HMGB1 Protein Health Human Immune response Infection Inflammation Inflammatory Inflammatory Response Intervention Keratitis Langerhans cell Ligands Lymphocyte Subset Mediator of activation protein Medical Economics Mitochondria Molecular Mus Natural Immunity Neutrophilic Infiltrate Onset of illness Pathogenesis Pattern Peptides Play Production Pseudomonas Pseudomonas aeruginosa Reactive Oxygen Species Recombinants Regulation Role Sepsis Sepsis Syndrome Severity of illness Signal Transduction Signaling Molecule Staging Surface TLR2 gene TLR4 gene Testing Toll-like receptors Up-Regulation Vision research Work adaptive immunity angiogenesis antimicrobial chemokine corneal epithelium cytokine economic impact insight macrophage member neutrophil new therapeutic target novel novel therapeutics pathogen prevent receptor research study response therapeutic target trafficking treatment strategy

项目摘要

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.

描述（由申请人提供）：铜绿假单胞菌 (P. aeurginosa) 是一种常见的机会致病菌，可引起细菌性角膜炎，尤其是在隐形眼镜使用过程中（每年 25,000-30,000 例，治疗费用估计为 15-3000 万美元）。拟议研究的目的是确定细菌性角膜炎发生的机制，特别是高迁移率族蛋白 1 (HMGB1)（一种原型警报素）的作用。 HMGB1 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/脓毒症晚期升高，被认为是疾病治疗的目标。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，并且具有与 Toll 样受体 (TLR) 和其他分子（例如晚期糖基化终产物受体 (RAGE)）结合的能力，我们假设和提供了初步支持数据，表明它对角膜炎症细胞反应具有显着的放大作用，是铜绿假单胞菌角膜炎的重要治疗靶点。本次竞争性更新中描述的实验是当前资助的 TLR4 研究的逻辑延续，因为我们将重点关注 HMGB1，这是一种与 TLR 配体和细胞因子相互作用并通过包括 TLR2、4 和 RAGE 在内的多种表面受体激活细胞的分子。尽管 HMGB1 是 DAMPS 家族中经过充分研究的成员，但尚无关于其在受感染角膜中作用的信息。因此，HMGB1如何奠定基础、放大宿主免疫反应并成为治疗靶标，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：将检验 HMGB1 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器功能的假设。具体目标 2：将检验 HMGB1 是新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，具有相当大的医学和经济影响。