Biology, immunology and therapy of Acanthamoeba keratitis

棘阿米巴角膜炎的生物学、免疫学和治疗

• 批准号: 7266853
• 负责人: Hassan Alizadeh
• 金额: $ 30.3万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-08-01 至 2009-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7266853
• 关键词: Acanthameba infection; Acanthamoeba; Acanthamoeba Keratitis; Address; Amoeba genus; Antigens; Apoptosis; Basement membrane; Behavior; Binding; Biology; Chinese Hamster; Cloning; Collagen Type IV; Complication; Cornea; Corneal Diseases; Data; Depth; Disease; Drug resistance; Endopeptidases; Enzymes; Epithelial Cells; Extracellular Matrix; Foundations; Generations; Glycoproteins; Goals; Human; Immunity; Immunology; Injection of therapeutic agent; Invaded; Invasive; Investigation; Keratitis; Laboratories; Lectin; Life; Mannose; Matrix Metalloproteinases; Membrane; Metalloproteases; Modality; Modeling; Necrosis; Organism; Parasites; Pathogenesis; Patients; Penetration; Peptide Hydrolases; Plasminogen Activator; Process; Production; Proteins; Range; Research; Role; Series; Soil; Stromal Cells; Subunit Vaccines; Therapeutic; Tissues; Vaccines; Vision; corneal epithelium; design; improved; inhibitor/antagonist; matrigel; Acanthameba infection; Acanthamoeba; Acanthamoeba Keratitis; Address; Amoeba genus; Antigens; Apoptosis; Basement membrane; Behavior; Binding; Biology; Chinese Hamster; Cloning; Collagen Type IV; Complication; Cornea; Corneal Diseases; Data; Depth; Disease; Drug resistance; Endopeptidases; Enzymes; Epithelial Cells; Extracellular Matrix; Foundations; Generations; Glycoproteins; Goals; Human; Immunity; Immunology; Injection of therapeutic agent; Invaded; Invasive; Investigation; Keratitis; Laboratories; Lectin; Life; Mannose; Matrix Metalloproteinases; Membrane; Metalloproteases; Modality; Modeling; Necrosis; Organism; Parasites; Pathogenesis; Patients; Penetration; Peptide Hydrolases; Plasminogen Activator; Process; Production; Proteins; Range; Research; Role; Series; Soil; Stromal Cells; Subunit Vaccines; Therapeutic; Tissues; Vaccines; Vision; corneal epithelium; design; improved; inhibitor/antagonist; matrigel

DESCRIPTION (provided by applicant): Acanthamoeba keratitis is a sight-threatening corneal disease caused by pathogenic free-living amoebae. The pathogenic cascade of Acanthamoeba keratitis involves a series of processes that include: (1) binding of the trophozoites to the corneal epithelial cells via lectin-glycoprotein interactions, (2) generation of cytopathic factors that destroy the corneal epithelium and stromal cells, (3) production of proteolytic enzymes that facilitate the invasion and penetration of trophozoites through the basement membrane and stroma, (4) elaboration of collagenolytic enzymes that degrade types I and IV collagens, which constitute the corneal matrix, (5) activation of corneal membrane metalloproteinases and, (6) induction of perineuritis. Stromal dissolution is a major blinding complication of Acanthamoeba keratitis. It will be important to determine what factors are involved in pathogenesis of stromal disease. In the present application, we are using different strategies to attack crucial steps in the pathogenic cascade in an effort to mitigate ongoing keratitis and preserve corneal tissues. Accordingly, therapeutic modalities are designed to inhibit invasion and destruction of corneal tissues after the organisms have invaded corneal matrix. The specific aims for this project are: 1) determine the role of Acanthamoeba plasminogen activator (aPA) in the pathogenesis of Acanthamoeba keratitis, 2) analyze the collagenolytic activity of the mannose-induced Acanthamoeba protein (133 -kDa), 3 ) determine if the mannose-induced Acanthamoeba protein (133-kDa) activate matrix metalloproteinases 4) determine feasibility of using the mannose-induced protein (133-kDa) and Acanthamoeba plasminogen activator (aPA) as immunogens for inducing immunity and mitigating the pathogenesis of Acanthamoeba infections. 5) Clone the 133-kDa protein and analyze the fragment that might be suitable for use as a subunit vaccine to induce better protection against Acanthamoeba infections. These studies utilize the Chinese hamster model of Acanthamoeba keratitis, that is similar to the human counterpart. Continued presence of Acanthamoeba keratitis and emergence of the drug resistant strains is underscoring the significance of this endeavor. The long-range goal of this project is to develop an anti-disease vaccine as a therapeutic adjunct for the management of Acanthamoeba keratitis.

描述（由申请人提供）：阿甘塔梅巴角膜炎是一种威胁性的角膜疾病，是由致病性自由活着的变形虫引起的。 The pathogenic cascade of Acanthamoeba keratitis involves a series of processes that include: (1) binding of the trophozoites to the corneal epithelial cells via lectin-glycoprotein interactions, (2) generation of cytopathic factors that destroy the corneal epithelium and stromal cells, (3) production of proteolytic enzymes that facilitate the invasion and penetration of trophozoites through地下膜和基质，（4）降解构成角膜基质的I型I和IV胶原的胶原式酶的阐述，（5）（5）角膜膜金属蛋白酶的激活，以及（6）诱导会阴炎。基质溶解是阿斯塔amoeba角膜炎的主要盲并发症。确定基质疾病发病机理涉及哪些因素很重要。在本应用中，我们正在使用不同的策略来攻击致病性级联反应的关键步骤，以减轻正在进行的角膜炎并保留角膜组织。因此，治疗方式旨在抑制生物体入侵角膜基质后角膜组织的侵袭和破坏。该项目的具体目的是：1）确定acanthamoeba纤溶酶原激活剂（APA）在Acanthamoeba角膜炎的发病机理中的作用，2）分析甘露糖诱导的acanthamoeba蛋白（133-kda）的胶原酶溶解活性（3）金属蛋白酶4）确定使用甘露糖诱导的蛋白（133-kDa）和acanthamoeba纤溶酶原激活剂（APA）作为免疫原子的可行性，以诱导免疫力并减轻阿斯塔amoeba感染的发病机理。 5）克隆133-kDa蛋白，并分析可能适合用作亚基疫苗的片段，以更好地诱导针对阿斯塔amoeba感染的保护。这些研究利用了与人类对应物相似的梯形角膜炎的中国仓鼠模型。持续存在acanthamoeba角膜炎和耐药菌株的出现是强调了这项努力的重要性。该项目的远距离目标是开发一种抗疾病疫苗作为治疗阿斯塔莫巴角膜炎的治疗辅助。