Role of Antimicrobial Peptides at the Ocular Surface

抗菌肽在眼表的作用

• 批准号: 8655861
• 负责人: ALISON M MCDERMOTT
• 金额: $ 36.87万
• 依托单位: UNIVERSITY OF HOUSTON
• 依托单位国家: 美国
• 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/8655861
• 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

Project Summary 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.

项目摘要 抗菌肽（AMP），例如防御素和cathelicidin是杀死的多功能分子 入侵的病原体和调节哺乳动物细胞活性，包括增殖，迁移和细胞因子 生产有助于调节免疫反应和伤口愈合。最近的研究已经建立 放大器在捍卫眼表面细菌感染（角膜炎）中的作用。对此的逻辑发展 进一步了解我们对眼表的AMP作用的理解是解决AMP在角膜炎中的作用 由真菌病原体引起。真菌角膜炎是一种威胁性疾病，发病率正在增加 （包括2004 - 2006年全球流行病），目前的治疗仅是中等有效的 结果通常比细菌角膜疾病更具破坏性。许多放大器具有强大的 在体外抗真菌活性，因此有可能对真菌病原体的先天防御作用，并且具有潜力 疗法。因此，关于AMP在防御真菌角膜炎中的作用的报道很少，因此 需要进行多种真菌病原体的深度研究来描述其参与并确定 可以利用这种方法来预防/治疗感染。将测试以下假设：AMP是 眼表面抗真菌感染所必需的。这将由三个 具体目标。在特定的目标1中，对人角膜上皮AMP表达的调节响应 普通的眼真菌将在体外研究并参与特定模式识别受体 阐明。在特定的目标2中，AMP的抗菌活性在溶液中，并将其束缚在表面上 将确定常见的眼真菌，并研究了撕裂成分对这项活动的影响。 这两个目标将有信息有关哪些内源表达的放大器在人类中活跃的 体内眼表面。最终目标将利用缺乏特定放大器的小鼠（遗传敲除或 siRNA敲低）在实验真菌性角膜炎模型中为AMPS IN VIVO发挥作用。也在 特定的目标3，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的正常宿主防御机制的重要信息 病原体并可能鉴定出用于预防和治疗真菌性角膜炎的新型抗真菌剂。