ECM Regulation of Ocular Surface Disease

ECM对眼表疾病的调节

基本信息

批准号：
10445477
负责人：
Pyong Woo Park
金额：
$ 44.25万
依托单位：
BOSTON CHILDREN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-04-01 至 2026-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10445477
关键词：
Adhesions Adhesives Automobile Driving Bacteria Bacterial Adhesion Bacterial Attachment Site Basement membrane Binding Binding Proteins Biochemical Biological Process Blindness Cell surface Cells Communicable Diseases Cornea Corneal Diseases Corneal Injury Data Disease Environment Epithelial Epithelial Cells Extracellular Matrix Extracellular Matrix Proteins Fibronectins Goals Gram-Negative Bacteria Heparan Sulfate Proteoglycan Heparin Binding Heparitin Sulfate Homeostasis In Vitro Incidence Infection Injury Keratitis Laminin Modernization Molecular Morbidity - disease rate Operative Surgical Procedures Parasites Pathogenesis Pathway interactions Patients Physiological Processes Pneumococcal Infections Public Health Receptor Signaling Regulation Resources Role Site Streptococcus pneumoniae Structure Testing Tissues Topical application Virulence Virus Vision base comparative corneal epithelium design fibrillogenesis gain of function in vivo microbial mouse model new therapeutic target ocular surface pathogen pathogenic bacteria pathogenic microbe prototype receptor syndecan tissue injury treatment duration

项目摘要

ABSTRACT Bacterial keratitis is a serious public health threat associated with significant ocular morbidity and is one of the major causes of blindness worldwide. By one estimate, the annual incidence of bacterial keratitis is approximately 500,000 patients worldwide. Even with modern day treatment, corneal infections can result in poor vision in 50% and surgical intervention in 12% of patients. Several Gram-positive and Gram-negative bacterial pathogens can infect the cornea and cause keratitis. Bacterial pathogens use all resources available to survive in the hostile host environment. Subversion of host extracellular matrix (ECM) components and their receptors as attachment sites is thought to be a common virulence mechanism shared by many bacteria. However, there are few data that clearly support this idea in vivo. We found in preliminary studies that deletion of syndecan-1 (Sdc1), a major cell surface heparan sulfate proteoglycan (HSPG) of epithelial cells, causes a gain of function in a mouse model of scarified corneal infection, where Sdc1-/- corneas are significantly less susceptible to Streptococcus pneumoniae infection. Topical administration of excess Sdc1 ectodomains or heparan sulfate (HS) significantly inhibits S. pneumoniae corneal infection, suggesting that HS chains of Sdc1 promote infection as a cell surface attachment receptor. However, S. pneumoniae does not interact with Sdc1 and Sdc1 is shed upon S. pneumoniae infection, indicating that Sdc1 does not directly support S. pneumoniae adhesion. Instead, Sdc1 promotes S. pneumoniae adhesion by driving the assembly of fibronectin (FN) fibrils in the corneal basement membrane to which S. pneumoniae attaches when infecting injured corneas. Excess Sdc1 ectodomains inhibit S. pneumoniae corneal infection by binding to the heparin-binding domain in FN, and interfering with S. pneumoniae binding to FN. Based on these data, this proposal will examine the overall hypothesis that specific ECM interactions coordinate the assembly of corneal basement membranes, and that certain bacterial pathogens of the ocular surface exploit these normal biological processes to promote their pathogenesis. This hypothesis will be tested in 3 Specific Aims. Aim 1 will define the structural basis of how HS inhibits bacterial corneal infection. Aim 2 will determine the significance and relevance of bacteria-induced Sdc1 shedding in corneal infection, and Aim 3 will elucidate the underlying mechanisms of how Sdc1 regulates FN fibrillogenesis in the corneal basement membrane. These studies are expected to uncover previously unknown functions of the ECM in the cornea and to establish a new integrated virulence pathway in bacterial keratitis.

抽象的细菌性角膜炎是一种严重的公共卫生威胁，与显着的眼部发病率相关，并且是其中之一全世界失明的主要原因。据估计，细菌性角膜炎的年发病率为全球约有 500,000 名患者。即使采用现代治疗，角膜感染也会导致 50% 的患者视力不佳，12% 的患者接受手术干预。几种革兰氏阳性和革兰氏阴性细菌病原体可感染角膜并引起角膜炎。细菌病原体使用所有可用资源在恶劣的宿主环境中生存。宿主细胞外基质（ECM）成分的颠覆及其作用受体作为附着位点被认为是许多细菌共有的共同毒力机制。然而，在体内却很少有数据明确支持这一想法。我们在初步研究中发现，删除 syndecan-1 (Sdc1) 是上皮细胞的一种主要细胞表面硫酸乙酰肝素蛋白多糖 (HSPG)，它会导致在划伤角膜感染的小鼠模型中获得功能，其中 Sdc1-/- 角膜显着减少易受肺炎链球菌感染。局部施用过量的 Sdc1 胞外域或硫酸乙酰肝素 (HS) 显着抑制肺炎链球菌角膜感染，表明 Sdc1 的 HS 链作为细胞表面附着受体促进感染。然而，肺炎链球菌不与 Sdc1 相互作用 Sdc1在肺炎链球菌感染后脱落，表明Sdc1不直接支持肺炎链球菌附着力。相反，Sdc1 通过驱动纤连蛋白 (FN) 原纤维的组装来促进肺炎链球菌粘附存在于肺炎链球菌感染受损角膜时附着的角膜基底膜中。过量的 Sdc1 胞外域通过与 FN 中的肝素结合域结合来抑制肺炎链球菌角膜感染，并且干扰肺炎链球菌与 FN 的结合。根据这些数据，本提案将审查总体情况假设特定的 ECM 相互作用协调角膜基底膜的组装，并且眼表的某些细菌病原体利用这些正常的生物过程来促进其发病。这一假设将在 3 个具体目标中得到检验。目标 1 将定义 HS 的结构基础抑制细菌角膜感染。目标 2 将确定细菌诱导的 Sdc1 在角膜感染中脱落，目标 3 将阐明 Sdc1 调节的潜在机制角膜基底膜中的 FN 纤维形成。这些研究预计将揭示以前角膜ECM的未知功能并在细菌中建立新的整合毒力途径角膜炎。