Role of Antimicrobial Peptides at the Ocular Surface

抗菌肽在眼表的作用

基本信息

批准号：
8321277
负责人：
ALISON M MCDERMOTT
金额：
$ 37.46万
依托单位：
UNIVERSITY OF HOUSTON
依托单位国家：
美国
项目类别：
财政年份：
2001
资助国家：
美国
起止时间：
2001-08-01 至 2017-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8321277
关键词：
Address Antifungal Agents Bacterial Infections Biological Assay Candida albicans Cell Culture Techniques Cells Clinical Contact Lenses Cornea Corneal Diseases Data Defensins Development Disease Enzyme-Linked Immunosorbent Assay Epidemic Epithelial Cells Experimental Models Fusarium Genetic Host Defense Mechanism Human Immune response In Vitro Incidence Infection Invaded Keratitis Knock-out Knockout Mice Knowledge Light Liposomes Literature Mammalian Cell Mediating Mission Mucins Mus Mycoses Orthologous Gene Outcome Pathogenesis Pattern recognition receptor Pharmacologic Substance Production Pseudomonas aeruginosa Reporting Research Reverse Transcriptase Polymerase Chain Reaction Role Small Interfering RNA Sodium Chloride Solutions Surface System Testing Therapeutic Topical application Vision Wound Healing antimicrobial antimicrobial peptide cathelicidin corneal epithelium cytokine fungus improved in vitro activity in vivo interest killings knock-down migration novel ocular surface pathogen pathogenic bacteria prevent response

项目摘要

DESCRIPTION (provided by applicant): Antimicrobial peptides (AMPs) such as defensins and cathelicidin are multifunctional molecules that kill invading pathogens and modulate mammalian cell activities including proliferation, migration and cytokine production thus helping to regulate immune responses and wound healing. Recent studies have established roles for AMPs in defending the ocular surface from bacterial infection (keratitis). A logical progression to this to further our understanding of AMP actions at the ocular surface is to address the role of AMPs in keratitis caused by fungal pathogens. Fungal keratitis is a vision threatening disease, which is increasing in incidence (including a world-wide epidemic in 2004-2006), current treatments are only moderately effective and outcomes are typically more devastating than with bacterial corneal disease. Many AMPs have potent antifungal activity in vitro so likely act in innate defense against fungal pathogens and have potential as therapeutics. There have been few reports on the role for AMPs in defense against fungal keratitis thus more in depth study encompassing multiple fungal pathogens is needed to delineate their involvement and identify ways this can be exploited to prevent/treat infection. The following hypothesis will be tested: AMPs are required for ocular surface innate defense against fungal infection. This will be addressed by three specific aims. In specific aim 1, modulation of human corneal epithelial AMP expression in response to common ocular fungi will be investigated in vitro and participation of specific pattern recognition receptors elucidated. In specific aim 2, the antimicrobial activity of AMPs in solution and tethered to surfaces against common ocular fungi will be determined, and the influence of tear components on this activity investigated. These two aims will be informative regarding which endogenously expressed AMPs are active at the human ocular surface in vivo. The final aim will utilize mice deficient in specific AMPs (either genetic knockouts or siRNA knockdown) to establish a role for AMPs in vivo in a model of experimental fungal keratitis. Also in specific aim 3, the potential of AMP-tethered liposomes as novel topical antifungal agents will be addressed. These studies will provide important information regarding normal host defense mechanisms against fungal pathogens and may identify novel antifungal agents for preventing and treating fungal keratitis. PUBLIC HEALTH RELEVANCE: Fungal keratitis is a vision threatening disease, which is increasing in incidence (including a world-wide epidemic in 2004-2006), current treatments are only moderately effective and outcomes are typically worse than with bacterial corneal disease. This proposal addresses the role of antimicrobial peptides in defending the ocular surface against fungal pathogens and their potential as novel, topical antifungal agents.

描述（由申请人提供）：抗菌肽（AMP），例如防御素和cathelicidin是多功能分子，可杀死入侵的病原体并调节哺乳动物细胞活性，包括增殖，迁移和细胞因子的产生，从而有助于调节免疫反应和伤口愈合。最近的研究已经确定了AMP在捍卫细菌感染（角膜炎）中的作用。对此的逻辑发展进一步，我们对眼部表面AMP作用的理解是解决AMP在由真菌病原体引起的角膜炎中的作用。真菌性角膜炎是一种威胁视力的疾病，发病率正在增加（包括2004 - 2006年的全球流行病），当前的治疗仅是适度有效的，并且结果通常比细菌角膜疾病更具破坏性。许多放大器在体外具有有效的抗真菌活性，因此很可能在对真菌病原体的天生防御中起作用，并且具有治疗剂的潜力。因此，很少有关于AMP在防御真菌角膜炎中的作用的报道，因此需要更多的深度研究，包括多个真菌病原体，以描绘它们的参与并确定可以利用这种方法来防止/治疗感染。将测试以下假设：眼表面防御真菌感染所必需的AMP。这将由三个特定目标解决。在特定的目标1中，将在体外调查对人角膜上皮AMP表达的调节，并阐明了特定模式识别受体的参与。在特定的目标2中，抗菌活性将确定溶液中的AMP，并束缚在针对常见的眼真菌的表面，并研究了撕裂成分对这项研究的影响。这两个目的将有信息，关于哪些内源表达的放大器在体内的人眼表面活性。最终目标将利用缺乏特定AMP的小鼠（遗传敲除或siRNA敲低）在实验性真菌角膜炎模型中为AMP的体内发挥作用。同样在特定的目标3中，将解决AMP系脂质体作为新型局部抗真菌剂的潜力。这些研究将提供有关针对真菌病原体的正常宿主防御机制的重要信息，并可能鉴定出用于预防和治疗真菌角膜炎的新型抗真菌剂。公共卫生相关性：真菌性角膜炎是一种威胁视力的疾病，发病率正在增加（包括2004年至2006年的全球流行病），当前的治疗仅是中等有效的，并且结果通常比细菌角膜疾病更糟。该建议探讨了抗菌肽在防御真菌病原体及其作为新型局部抗真菌剂的潜力的作用。