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: 8345535
• 负责人: Rafael Ufret-Vincenty
• 金额: $ 39.75万
• 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/8345535
• 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 treatment; 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

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. PUBLIC HEALTH RELEVANCE: A variant in complement factor H significantly increases the risk for age-related macular degeneration (AMD), a very prevalent blinding disorder. Our goal in this proposal is to understand how Cfh variants are involved in the early mechanisms of disease in AMD. We hope to use this information to identify new targets for early therapeutic intervention, in order to modify the disease course before irreversible vision loss has occurred.

描述（由申请人提供）：与年龄相关的黄斑变性（AMD）是美国60岁以上人群不可逆转的法律失明的主要原因，其中超过180万美国人受晚期疾病的影响。对于该疾病的晚期萎缩形式，没有经过证明的有效疗法。同样，尽管抗血管内皮生长因子剂最近出现了，但“湿” AMD的临床结果仍然是最佳的。对生活质量的影响很严重，通常会导致生活方式变化和重大变化 焦虑和沮丧。最近的证据表明，慢性炎症可能针对氧化损伤产生的视网膜下碎片，在疾病过程中可能很重要。遗传研究一直表明，补体因子H（CFH）的变体是补体激活的重要调节剂，是AMD的强大危险因素。但是，CFH与疾病过程相关的机制尚不清楚。我们最近生成了对与AMD相关的CFH变体进行建模的嵌合CFH转基因小鼠系。这些小鼠会产生与早期AMD一致的发现。它们还具有在后极累积视网膜下巨噬细胞的倾向。这最后的发现令人着迷，因为一些研究表明巨噬细胞可能对AMD有保护性，而另一些研究则暗示它们促进了疾病的进展。在此提案中，我们计划使用CFH转基因小鼠解决三个问题：1。CFH变体在调节不同之后调节炎症中的作用 急性与慢性炎症刺激，2。确定哪些分子相互作用受CFH变体的影响（CFH与C反应蛋白或与糖胺聚糖的相互作用，或与其他CFH分子的相互作用），或与AMD和3的作用相关。变体。在研究结束时，我们希望对AMD的早期发病机理有更好的了解，以确定潜在的早期干预治疗靶标，并为该疾病产生更强大的动物模型。 公共卫生相关性：补体因子H的一种变体显着增加了与年龄相关的黄斑变性（AMD）的风险，这是一种非常普遍的盲目疾病。我们在该提案中的目标是了解CFH变体如何参与AMD疾病的早期机制。我们希望使用这些信息来确定早期治疗干预的新目标，以便在发生不可逆转的视力丧失之前修改疾病病程。