Inflammasome Activation in Geographic Atrophy

描述(申请人提供)：地理性萎缩(GA)是一种无法治疗的晚期老年性黄斑变性(AMD)，其特征是视网膜色素上皮(RPE)退化。无论是促进这种RPE退化的机制，还是最终导致失明的GA离心性膨胀的基础都没有解决。GA发病机制的这种神秘性质排除了FDA批准的任何针对100万被诊断为GA的美国人和数百万面临发展为GA风险的美国人的治疗方法的开发。在新的和令人兴奋的研究中，我们发现了GA患者人眼RPE中NLRP3炎症体复合体的非传统免疫激活(Tarallo等人。细胞2012)，在RNase DICER1缺乏期间，响应有毒的非编码Alu RNA的特定积累而发生，并诱导RPE退化(Kaneko等人。《自然》2011)。这一令人惊讶的发现在非免疫细胞中发现了病理性炎症小体激活，这是理解GA发病机制和阐明决定视网膜活力的基本效应途径的关键一步。我们的发现引入了自身免疫的一个新定义：NLRP3炎症体对自体Alu RNA的RPE激活代表了炎症体激活到内源性的第一个描述，同时在经典免疫的特权眼环境中引起了病理。关键是，沿着NLRP3炎性小体激活的多个分子步骤的阻断阻止了RPE细胞的死亡，从而为减轻全球GA的负担提供了一个重要的基于机制的策略。然而，我们仍然缺乏对其他AMD相关应激源是否也导致GA中炎症体激活的完整了解，以及如果是这样的话，这些机制是如何汇聚到导致RPE变性的共同效应通路上的。对这些机制的严格定义对于加强我们对GA的分子驱动因素的理解和开发合理的治疗方法至关重要。我们将通过下列目标提供新的功能见解：(1)构建已知的AMD相关应激源和NLRP3炎症体激活标记物的时空图；(2)通过已知的GA相关应激反应，阐明炎症体激活的分子机制；(3)在AMD的急慢性动物模型中，确定阻断炎症体机械及其效应通路是否抑制RPE退变。这些研究将阐明GA的分子和生化基础的新方面，并有助于验证可转化为临床试验的分子靶向策略。因此，这项建议与NEI的视网膜疾病计划战略计划的年度目标保持一致。

DESCRIPTION (provided by applicant): Geographic atrophy (GA) is an untreatable advanced form of age-related macular degeneration (AMD) that is characterized by degeneration of the retinal pigmented epithelium (RPE). Neither the mechanisms that promote this RPE degeneration nor the basis for the centrifugal expansion of GA that can ultimately lead to blindness have been resolved. This enigmatic nature of GA pathogenesis has precluded the development of any FDA-approved therapy for the one million Americans diagnosed with GA and the millions more at risk of developing GA. In new and exciting studies, we discovered an unconventional immune activation of the NLRP3 inflammasome complex in the RPE of human eyes with GA (Tarallo et al. Cell 2012) that occurs in response to a specific accumulation of toxic non-coding Alu RNAs during deficiency in the RNase DICER1 and induces RPE degeneration (Kaneko et al. Nature 2011). This surprising finding of pathologic inflammasome activation in a non-immune cell is a critical step in understanding GA pathogenesis and elucidating the essential effector pathways that determine retinal vitality. Our findings, which introduce a novel definition of auto-immunity: The RPE activation of the NLRP3 inflammasome in response to self-derived Alu RNAs represents the first description of inflammasome activation to endogenous, all the while causing pathology in a classically immune privileged ocular milieu. Crucially, blockade at multiple molecular steps along NLRP3 inflammasome activation blocked RPE cell death, thus providing an important mechanism-based strategy to alleviating the worldwide burden of GA. However, we still lack an integrated understanding of whether other AMD-related stressors also cause inflammasome activation in GA, and if so, precisely how these mechanisms converge upon common effector pathways that induce RPE degeneration. A rigorous definition of these mechanisms is crucial to enhancing our understanding of the molecular drivers of GA and to developing rational treatments. We will provide novel functional insights into how dysregulated NLRP3 inflammasome activation contributes to GA pathogenesis and develop a novel therapeutic strategy via the following Aims: (1) Generate a spatiotemporal map of known AMD-related stressors and markers of NLRP3 inflammasome activation in relation to the locus of pathology in GA and early AMD eyes; (2) Decipher the molecular mechanisms underlying inflammasome activation by known GA-associated stresses; (3) Determine whether blockade of inflammasome machinery and its effector pathways in acute and chronic animal models of AMD inhibit RPE degeneration. These studies will illuminate novel aspects of the molecular and biochemical bases of GA, and help validate a molecular targeting strategy that could be translated into clinical trials. As such, this proposal is aligned with the -year goals of the NEI's Retinal Diseases Program strategic plan.