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CAP37 and ocular inflammation

CAP37 和眼部炎症

基本信息

批准号：
8135325
负责人：
Heloise. ANNE Pereira
金额：
$ 35.16万
依托单位：
UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-09-30 至 2013-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8135325
关键词：
Acute Anti-Bacterial Agents Anti-Inflammatory Agents Anti-inflammatory Antibiotics Bacteria Bacterial Eye Infections Bacterial Infections Biological Blindness Cell Adhesion Molecules Cell Line Cell physiology Cells Chemotaxis Chronic Cicatrix Ciliary epithelium Cornea Corneal Stroma Cytoplasmic Granules Data Data Analyses Development Disclosure Emigrations Enzyme-Linked Immunosorbent Assay Epithelial Epithelial Cell Proliferation Epithelial Cells Event Extracellular Matrix Eye Eye Infections Flow Cytometry Healed Host Defense Human Immune Immunohistochemistry Infection Inflammation Inflammation Mediators Inflammatory Inflammatory Response Invaded Keratitis Laboratories Lead Leukocytes Location Measures Mediating Mediator of activation protein Microglia Modeling Molecular Mus Oryctolagus cuniculus Peptides Perforation Play Property Protein Kinase C Proteins Pseudomonas aeruginosa Public Health RNA Interference Reaction Regulation Research Reverse Transcriptase Polymerase Chain Reaction Role Signal Transduction Signaling Molecule Site Smooth Muscle Myocytes Staining method Stains Staphylococcus aureus Stimulus System Techniques Testing Tissues Ulcer Up-Regulation Vascular Endothelial Cell Vascular Endothelium Wound Infection antimicrobial bactericide base bulbar conjunctiva corneal epithelial cell adhesion corneal epithelium cytokine design healing in vivo inhibitor/antagonist limbal macrophage migration monocyte mouse model neutralizing antibody neutrophil novel novel therapeutics pathogen response ward

项目摘要

DESCRIPTION (provided by applicant): This application is designed to investigate the role of the inflammatory mediator, CAP37, in ocular inflammation. CAP37 was recently identified in the eye in response to bacterial infection. Surprisingly, its localization was not confined to the neutrophil (PMN), where it is known to be constitutively expressed, but it was also found induced in corneal epithelial cells, and vascular endothelial cells of the limbal and ciliary vessels. There are many inflammatory-associated biological activities regulated by CAP37 that confer on this molecule a role in innate host defense against invading pathogens. CAP37 is a potent antibiotic, promotes monocyte chemotaxis, and has immunomodulatory effects on host cells including corneal epithelial cells. The induction of a host defense molecule in the outermost layers of the eye and in the vascular endothelium in response to infection, suggests that it could play a key role in regulating inflammation and healing in the cornea and in the long term form the basis for developing new therapeutics for certain eye infections. It is our hypothesis that CAP37, either released by PMNs or induced in corneal epithelial cells at the site of infection, plays a pivotal role in the inflammatory response of the cornea to infection. We hypothesize that it accomplishes this through a novel, dual mechanism of action based on its antibiotic/anti-inflammatory and immunomodulatory properties. Aim 1: To test the hypothesis that the regulation of proliferation, chemotaxis, and adhesion of corneal epithelial cells in ocular inflammation is dependent on CAP37 and is mediated through the intracellular signaling molecule protein kinase C, we will use techniques that include immunohistochemistry, pharmacological inhibitors, and RNA interference. Aim 2: To test the hypothesis that CAP37 is a biologically relevant mediator in host defense in the eye, we will measure the induction and identity of inflammatory cells, mediators, cytokines, and adhesion molecules in response to the administration of CAP37, its bioactive peptides, and neutralizing antibodies into the corneal stroma. Flow cytometry, ELISA, immunohistochemistry, and RT-PCR will be used to analyze data. Aim 3: To test the hypothesis that the anti-inflammatory and immunomodulatory properties of CAP37 are important for host defense in ocular infection we will use CAP37 and its bioactive peptides in a murine model of Pseudomonas aeruginosa keratitis to determine in vivo efficacy. Relevance to public health: Once corneal integrity is breached, prompt treatment with antibiotics is required to halt the development of infection and harmful sequelae such as ulceration, perforation, scarring, and loss of vision. Unfortunately, the antibiotics currently available for ophthalmic use have serious limitations. We believe our findings will help develop new therapies for treating wounds and infections of the eye based on the biological molecule CAP37 and its bioactive peptides.

描述（由申请人提供）：本申请旨在研究炎症介质CAP 37在眼部炎症中的作用。CAP 37最近在眼睛中被鉴定为响应细菌感染。令人惊讶的是，它的定位不限于中性粒细胞（PMN），在那里它是已知的组成型表达，但它也被发现诱导角膜上皮细胞，和血管内皮细胞的角膜缘和睫状血管。有许多炎症相关的生物活性由CAP 37调节，赋予该分子在先天宿主防御入侵病原体中的作用。CAP 37是一种有效的抗生素，促进单核细胞趋化性，并对宿主细胞包括角膜上皮细胞具有免疫调节作用。针对感染，在眼睛最外层和血管内皮中诱导宿主防御分子，这表明它可以在调节角膜炎症和愈合方面发挥关键作用，并从长远来看形成开发新疗法的基础针对某些眼部感染。我们的假设是，由PMN释放或在感染部位的角膜上皮细胞中诱导的CAP 37在角膜对感染的炎症反应中起关键作用。我们假设它通过基于其抗生素/抗炎和免疫调节特性的新型双重作用机制来实现这一点。目标1：为了验证这一假设，即在眼部炎症中角膜上皮细胞的增殖，趋化性和粘附的调节依赖于CAP 37，并通过细胞内信号分子蛋白激酶C介导，我们将使用包括免疫组织化学，药理学抑制剂和RNA干扰的技术。目标二：为了检验CAP 37是眼睛中宿主防御中的生物学相关介质的假设，我们将测量响应于将CAP 37、其生物活性肽和中和抗体施用到角膜基质中的炎症细胞、介质、细胞因子和粘附分子的诱导和身份。将使用流式细胞术、ELISA、免疫组织化学和RT-PCR分析数据。目标3：为了检验CAP 37的抗炎和免疫调节特性对于眼部感染中的宿主防御是重要的这一假设，我们将在铜绿假单胞菌角膜炎的鼠模型中使用CAP 37及其生物活性肽来确定体内功效。与公共卫生的相关性：一旦角膜的完整性被破坏，就需要及时用抗生素治疗，以阻止感染和有害后遗症的发展，如溃疡、穿孔、瘢痕和视力丧失。不幸的是，目前可用于眼科使用的抗生素具有严重的局限性。我们相信我们的发现将有助于开发基于生物分子CAP 37及其生物活性肽的治疗眼睛伤口和感染的新疗法。