Autoimmunity and Age-Related Macular Degeneration

自身免疫和年龄相关性黄斑变性

• 批准号: 8708878
• 负责人: ALESSANDRO IANNACCONE
• 金额: $ 36.75万
• 依托单位: UNIVERSITY OF TENNESSEE HEALTH SCI CTR
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8708878
• 关键词: Address; Adoptive Transfer; Age related macular degeneration; Aging; Animal Model; Antibodies; Antigens; Appearance; Autoantibodies; Autoantigens; Autoimmune Process; Autoimmunity; Back; Bruch' s basal membrane structure; Choroid; Chronic; Clinical Trials; Collection; Complex; Development; Disease; Disease Marker; Disease Progression; Elderly; Etiology; Event; Exhibits; Fundus; Human; Immune; Immune system; Immunoglobulin G; Immunoprecipitation; Inflammation; Inflammatory; Investigation; Knock-out; Knockout Mice; Lead; Lesion; Link; Mass Spectrum Analysis; Mediating; Modeling; Monitor; Motion; Mus; Pathogenesis; Patients; Pattern; Phenotype; Play; Proteins; Quality of life; Risk Marker; Role; SOD2 gene; Sampling; Series; Serum; Severities; Speed; Staging; Structure of retinal pigment epithelium; Testing; Time; Tissues; Transgenic Mice; Translating; Vision; Western Blotting; Wild Type Mouse; autoreactivity; base; early onset; human tissue; in vivo; macula; mouse model; research study

DESCRIPTION (provided by applicant): Age-related macular degeneration (AMD) is a highly prevalent, multifactorial, polygenic complex disease. It is now widely accepted that inflammation and the immune system play a direct role in the pathogenesis of AMD. As inflammation builds up in aging and, much more so, in AMD, we hypothesize that a vicious cycle is set in motion that exposes macular tissues to an increasing amount of inflammatory and immune-mediated damage. We propose that this mechanism is critical to AMD development and progression. We have strong evidence that patients with early and advanced AMD express auto-antibodies (auto-Abs) against macular human tissue antigens significantly more commonly and more intensely than elderly controls. However, having shown this does not prove that the auto-Abs have a direct role in contributing to disease development and/or progression. To understand the role of auto-Abs in AMD, it is essential to discover the identity of their targets, and provide prof of a causal link between disease and presence of auto-Abs. To tackle these critically important questions, we propose the following series of Aims: 1) To discover the identity of all statisticall significant macular antigens identified in our preliminary investigations and test the hypothesis that wild-type (WT) mice immunized against these antigens develop auto-Abs towards them and changes consistent with an AMD phenotype. 2) To test the hypothesis that auto-Abs that develop in an early-onset murine model of AMD can be used to accelerate disease appearance and increase its severity in a late-onset model via adoptive transfer of serum IgG. 3) To test the hypothesis that similar autoimmune reactivity patterns occur not only across species but also across animal models of AMD, and to establish a relationship between time course of auto-Ab development and time of onset of phenotypes. These studies will allow us to discover targets of autoreactivity in AMD, investigate commonalities (and differences) across species and models, test the causality of the autoimmune hypothesis in AMD, define an "autoreactivity sequence", identify early disease markers and progression risk markers, and develop a much more refined pathogenic framework for the role of autoimmunity in AMD. We predict that these studies will ultimately pave the way toward using the existing AMD models and those that we plan to induce to investigate and develop new treatments for the manifestations of AMD, and that it will be possible to translate these treatments back to bedside in human clinical trials.

描述（由申请人提供）：与年龄相关的黄斑变性（AMD）是一种高度普遍的多因素，多基因复杂疾病。现在，炎症和免疫系统在AMD的发病机理中起着直接的作用已被广泛接受。随着炎症在衰老中累积，而在AMD中，我们假设一个恶性循环开始运动，使黄斑组织暴露于越来越多的炎症和免疫介导的损伤。我们建议这种机制对于AMD的发展和发展至关重要。我们有强有力的证据表明，早期和晚期AMD表达自身抗体（自动抗体）对黄斑人体组织抗原的患者比老年对照组明显更常见，更强烈。但是，证明这一点并不能证明自动AB在促进疾病发展和/或进展方面具有直接作用。要了解自动AB在AMD中的作用，必须发现其目标的身份，并提供疾病与自动ABS存在之间的因果关系的教授。为了解决这些至关重要的问题，我们提出了以下一系列目的：1）在我们的初步研究中发现所有统计量显着的黄斑抗原的身份，并检验了野生型（WT）小鼠对这些抗原对这些抗原产生自动对其及其与AMD概况一致的变化的假设。 2）为了检验以下假设：在早期发作的AMD鼠模型中发展的自动AB可以通过血清IgG的过继转移来加速疾病的外观并在晚期模型中增加其严重程度。 3）测试假设，即类似的自身免疫反应模式不仅发生在各种物种之间，而且还发生了AMD的动物模型，并在自动-AB发育的时间过程与表型发作之间建立了关系。这些研究将使我们能够发现AMD中的自动反应性靶标，调查物种和模型之间的共同点（和差异），测试AMD自身免疫性假设的因果关系，定义了“自动反应序列”，确定早期疾病标志物和进展标志物，并发展出更加精确的病原框架，以使其具有更高的正常框架，以实现Ausoimmmune的作用。我们预测，这些研究最终将为使用现有的AMD模型以及我们计划诱使研究和开发AMD表现的新疗法的方法铺平道路，并且可以将这些治疗方法转换为人类临床试验中的床边。