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

• 批准号: 8546385
• 负责人: Rafael Ufret-Vincenty
• 金额: $ 37.76万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 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/8546385
• 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' 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

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）：视网膜相关性黄斑变性（AMD）是美国60岁以上人群中不可逆法律的失明的主要原因，超过180万美国人受晚期疾病影响。对于这种疾病的晚期萎缩形式，还没有被证明有效的治疗方法。此外，尽管抗血管内皮生长因子药物最近出现，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急剧变化， 焦虑和抑郁。最近的证据表明，慢性炎症，可能是针对视网膜下的碎片产生的氧化损伤，可能是重要的疾病过程。遗传研究一致表明，补体因子H（Cfh）的变异体（补体激活的重要调节因子）是AMD的一个强风险因素。然而，Cfh与疾病过程相关的机制还不清楚。我们最近产生了嵌合Cfh转基因小鼠系，其模拟与AMD相关的Cfh变体。这些小鼠的发现与早期AMD一致。它们还具有在后极中积聚视网膜下巨噬细胞的倾向。最后一个发现是有趣的，因为一些研究表明巨噬细胞可能对AMD有保护作用，而另一些研究则暗示它们促进了疾病的进展。本研究计划利用Cfh转基因小鼠解决三个问题：1. Cfh变异体在调节不同炎症后的作用 急性与慢性炎症刺激，2.确定哪些分子相互作用受到Cfh变体的影响（Cfh与c-反应蛋白、或与糖胺聚糖、或与其他Cfh分子的相互作用），以及这种作用如何与AMD相关，以及3.确定巨噬细胞在AMD发病机制中的作用，以及Cfh变体如何影响巨噬细胞。在研究结束时，我们希望更好地了解AMD的早期发病机制，确定早期干预的潜在新治疗靶点，并为该疾病建立更强大的动物模型。