Autoimmunity and Age-Related Macular Degeneration

自身免疫和年龄相关性黄斑变性

• 批准号: 8895335
• 负责人: FRANCESCO GIORGIANNI
• 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 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8895335
• 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）：视网膜相关性黄斑变性（AMD）是一种高度流行的多因素多基因复杂疾病。目前普遍认为炎症和免疫系统在AMD的发病机制中起直接作用。随着炎症在衰老中的积累，在AMD中更是如此，我们假设一个恶性循环正在启动，使黄斑组织暴露于越来越多的炎症和免疫介导的损伤。我们认为这种机制对AMD的发展和进展至关重要。我们有强有力的证据表明，早期和晚期AMD患者比老年对照组更普遍和更强烈地表达针对黄斑人类组织抗原的自身抗体（自身抗体）。然而，这并不能证明自身抗体在促进疾病发展和/或进展中具有直接作用。为了了解自身抗体在AMD中的作用，必须发现其靶点的身份，并提供疾病和自身抗体存在之间的因果关系。为了解决这些至关重要的问题，我们提出了以下一系列的目的：1）发现在我们的初步研究中鉴定的所有具有免疫学意义的黄斑抗原的身份，并测试针对这些抗原免疫的野生型（WT）小鼠产生针对它们的自身抗体和与AMD表型一致的变化的假设。2)为了检验以下假设：在早发性AMD鼠模型中产生的自身抗体可用于通过血清IgG的过继转移加速疾病的出现并增加其在迟发性模型中的严重程度。3)为了检验不仅在物种之间而且在AMD动物模型之间发生相似的自身免疫反应模式的假设，并建立自身抗体发展的时间过程与表型发作时间之间的关系。这些研究将使我们能够发现AMD中自身反应性的靶点，研究跨物种和模型的共性（和差异），测试AMD中自身免疫假说的因果关系，定义“自身反应性序列”，鉴定早期疾病标志物和进展风险标志物，并为自身免疫在AMD中的作用开发更精细的致病框架。我们预测，这些研究最终将为使用现有的AMD模型和我们计划诱导的模型来研究和开发针对AMD表现的新治疗方法铺平道路，并且将有可能将这些治疗方法转化回人类临床试验的床边。