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Role of complement factor H and immunity in AMD: a novel transgenic model

补体因子 H 和免疫在 AMD 中的作用：一种新型转基因模型

基本信息

批准号：
8708875
负责人：
Rafael Ufret-Vincenty
金额：
$ 38.96万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-30 至 2017-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8708875
关键词：
A Mouse Acute Address Affect Age related macular degeneration Age-Years American Animal Disease Models Animal Model Anxiety Atrophic Binding Blindness Bruch&apos s basal membrane structure Chemotactic Factors Choroidal Neovascularization Chronic Clinical Collagen Complement Complement Activation Complement Factor H Cytoplasmic Granules Data Deposition Development Diet Disease Disease Progression Early Intervention Environmental Risk Factor Epidemiology Event Exposure to Fundus Genes Genetic Genetic Risk Glycosaminoglycans Goals Histopathology Human Hydroquinones Immune response Immune system Immunity Immunization Inflammation Inflammatory Inflammatory Response Injury Knowledge Laser injury Lead Legal Blindness Life Style Light Lighting Lipofuscin Mental Depression Modeling Molecular Mus Outcome Oxidative Stress Pathogenesis Phenotype Play Precipitation Predisposition Process Proteins Quality of life Regulation Research Retina Retinal Risk Risk Factors Role Serum Serum Albumin Single Nucleotide Polymorphism Smoking Stimulus Structure of retinal pigment epithelium Testing Therapeutic Intervention Tissues Toxin Transgenic Mice Transgenic Model Transgenic Organisms Variant Vascular Endothelial Growth Factors Vision adduct advanced disease age effect apolipoprotein B-100 base cigarette smoking cytokine effective therapy genetic risk factor geographic atrophy hydroquinone in vivo macrophage mouse model neovascular new therapeutic target novel novel therapeutics oxidative damage response risk variant

项目摘要

DESCRIPTION (provided by applicant): Age-related macular degeneration (AMD) is the leading cause of irreversible legal blindness in people over 60 years of age in the US, with over 1.8 million Americans affected by advanced disease. There is no proven effective therapy for the advanced atrophic form of the disease. Also, despite the recent advent of anti- vascular endothelial growth factor agents, the clinical outcomes for "wet" AMD remain suboptimal. The impact on quality of life is severe, often leading to drastic changes in life-style and significant anxiety and depression. Recent evidence suggests that chronic inflammation, likely directed towards subretinal debris generated from oxidative damage, may be important in the disease process. Genetic studies have consistently shown that a variant in complement factor H (Cfh), an important regulator of complement activation, is a strong risk factor for AMD. However, the mechanism by which Cfh is associated to the disease process is not well understood. We have recently generated chimeric Cfh transgenic mouse lines that model the Cfh variants associated to AMD. These mice develop findings consistent with early AMD. They also have a propensity to accumulate subretinal macrophages in the posterior pole. This last finding is intriguing, since some studies suggest that macrophages may be protective against AMD, while others imply that they promote disease progression. In this proposal we plan to use the Cfh transgenic mice to address three issues: 1. the role of the Cfh variants in regulating inflammation after different acute vs. chronic inflammatory stimuli, 2. determine which molecular interactions are affected by the Cfh variant (interactions of Cfh with c-reactive protein, or with glycosaminoglycans, or with other Cfh molecules), and how this effect may be relevant to AMD, and 3. determine the role of macrophages in the pathogenesis of AMD, and how that is affected by the Cfh variants. At the end of the study we hope to have a better understanding of the early pathogenesis of AMD, to have identified potential new therapeutic targets for early intervention, and to have generated a more robust animal model for the disease.

描述（由申请人提供）：在美国，年龄相关性黄斑变性（AMD）是导致60岁以上人群不可逆转的法定失明的主要原因，超过180万美国人患有晚期疾病。对于这种疾病的晚期萎缩性形式，目前还没有被证明有效的治疗方法。此外，尽管最近出现了抗血管内皮生长因子药物，但“湿性”AMD的临床结果仍然不理想。对生活质量的影响是严重的，往往导致生活方式的剧烈变化和重大变化