Initiating Events in AMD: a mouse model for the human disease

AMD 的起始事件：人类疾病的小鼠模型

• 批准号: 8316273
• 负责人: JOE Gilbert HOLLYFIELD
• 金额: $ 39.25万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-02 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8316273
• 关键词: Age; Age related macular degeneration; Age-Years; Aging; Albumins; Animal Model; Antibodies; Antigens; Autoantibodies; Binding; Blood Circulation; Bruch' s basal membrane structure; Carbon; Cells; Characteristics; Complement; Complement 3; Complement 3a; Complement 3b; Complement 4b; Complement Activation; Complement Factor B; Complement Suppression; Coupled; Deposition; Developed Countries; Development; Disease; Dissection; Docosahexaenoic Acids; Drusen; Elderly; Environment; Epitopes; Event; Eye; Generations; Genes; Goals; Grant; Haptens; Immune; Immune response; Immune system; Immunization; Immunoglobulin G; Immunoglobulin M; Individual; Inflammatory; Intake; Intervention; Lead; Lectin; Lesion; Light; Link; Lipids; Mediating; Modeling; Monoclonal Antibodies; Mus; Oral; Outcome; Outcome Study; Oxygen; Pathogenesis; Pathology; Pathway interactions; Patients; Photoreceptors; Plasma; Plasma Proteins; Polyunsaturated Fatty Acids; Preclinical Testing; Prevention; Process; Proteins; Relative (related person); Research; Retina; Retinal; Retinol Binding Proteins; Role; Route; Scourge; Serum Albumin; Signal Transduction; Site; Source; Staging; Structure of retinal pigment epithelium; Testing; Therapeutic; Therapeutic Intervention; Time; Tissues; Vision; adduct; alternative pathway complement C3 convertase; arm; autoimmune uveitis; base; complement pathway; geographic atrophy; human disease; innovation; insight; mouse model; normal aging; novel; novel therapeutics; oral tolerance; oxidation; oxidative damage; prevent

DESCRIPTION (provided by applicant): Age-related macular degeneration (AMD) is a scourge of the elderly, with some stage of this potentially blinding disease present in approximately a third of individuals over 75 years of age in the US. There is substantial evidence that AMD is an inflammatory disease involving dysregulation of the complement pathway. We found that the hapten, CEP (carboxyethylpyrrole), generated by oxidative damage to docosahexaenoic acid (DHA), is present as an adduct on drusen proteins in AMD donor eyes. In addition, autoantibodies against CEP were more abundant in the circulation (plasma) of individuals with AMD than in age-matched individuals without AMD. Because DHA is abundant in the outer retina where light and high oxygen levels provide a permissive environment for oxidative damage, this tissue is a likely source of CEP-adducts. Since CEP-adducts is antigenic, we speculated that as the outer retina generates these adducts, the immune system becomes responsive to these new epitopes and over time begins to attack the cells that are the source of this fragment. To test this hypothesis we immunized normal mice with CEP-adducted mouse serum albumin (CEP-MSA). Our prediction was that systemic immunization with CEP would sensitize mice to endogenous CEP-adducts generated in the outer retina during the normal course of aging. In turn the immune system would respond by attacking the cells where CEP epitopes are most readily generated. We found that immunized mice develop antibodies to CEP, fix complement component-3 in Bruch's membrane, accumulate drusen below the RPE during aging, and develop lesions in the RPE mimicking geographic atrophy, the end-stage condition characteristic of dry AMD. The research proposed here uses this mouse model for mechanistic studies on the role of complement activation pathways in producing the pathology, the role of antibody in causing the lesions observed, and the possibility of prevention of the lesions through manipulation of complement activation or suppression of the pathology with oral tolerance. Outcomes from these studies have the potential to lead to the identification of new therapeutic pathways to prevent AMD.

描述（由申请人提供）：年龄相关性黄斑变性 (AMD) 是老年人的祸害，在美国，大约三分之一的 75 岁以上的人患有这种潜在致盲疾病的某个阶段。有大量证据表明 AMD 是一种涉及补体途径失调的炎症性疾病。我们发现，由二十二碳六烯酸 (DHA) 氧化损伤产生的半抗原 CEP（羧乙基吡咯）在 AMD 供体眼中以玻璃膜疣蛋白的加合物形式存在。此外，AMD 患者循环（血浆）中的 CEP 自身抗体比年龄匹配的非 AMD 患者更丰富。由于 DHA 在外视网膜中含量丰富，光和高氧水平为氧化损伤提供了宽松的环境，因此该组织可能是 CEP 加合物的来源。由于 CEP 加合物具有抗原性，我们推测当外视网膜产生这些加合物时，免疫系统会对这些新表位产生反应，并随着时间的推移开始攻击作为该片段来源的细胞。为了检验这一假设，我们用 CEP 加合的小鼠血清白蛋白 (CEP-MSA) 免疫正常小鼠。我们的预测是，CEP 全身免疫将使小鼠对正常衰老过程中视网膜外层产生的内源性 CEP 加合物敏感。反过来，免疫系统会通过攻击最容易产生 CEP 表位的细胞来做出反应。我们发现，免疫小鼠会产生针对 CEP 的抗体，将补体成分 3 固定在 Bruch 膜中，在衰老过程中在 RPE 下方积聚玻璃膜疣，并在 RPE 中出现类似于地图样萎缩（干性 AMD 的终末期症状）的病变。这里提出的研究使用这种小鼠模型进行机制研究，研究补体激活途径在产生病理学中的作用、抗体在引起观察到的病变中的作用，以及通过操纵补体激活或通过口服耐受抑制病理学来预防病变的可能性。这些研究的结果有可能导致确定预防 AMD 的新治疗途径。