Inflammasome Activation in Geographic Atrophy

描述（由申请人提供）：地理萎缩（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）变性。无论是促进这种RPE变性的机制，还是最终导致失明的GA离心膨胀的基础都没有得到解决。GA发病机制的这种神秘性质阻碍了fda批准的任何针对100万确诊为GA的美国人和数百万有患GA风险的美国人的治疗。在新的和令人兴奋的研究中，我们发现了一种非常规的免疫激活NLRP3炎性体复合物在人眼与GA的RPE （Tarallo等）。Cell 2012)，在RNase DICER1缺乏期间，毒性非编码Alu rna特异性积累，并诱导RPE变性（Kaneko等）。自然2011)。在非免疫细胞中发现病理性炎性体激活是理解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。我们的研究结果引入了自身免疫的新定义：NLRP3炎性小体的RPE激活是对自源性Alu rna的反应，首次描述了炎性小体对内源性的激活，同时在典型的免疫特权眼环境中引起病理。至关重要的是，沿NLRP3炎性体激活的多个分子步骤的阻断阻断了RPE细胞死亡，从而为减轻GA的全球负担提供了一种重要的基于机制的策略。然而，我们仍然缺乏对其他amd相关的应激源是否也会导致GA中的炎性体激活的综合理解，如果是的话，这些机制如何精确地聚集在诱导RPE变性的常见效应途径上。严格定义这些机制对于加强我们对GA分子驱动因素的理解和制定合理的治疗方法至关重要。我们将通过以下目标提供新的功能见解，了解失调的NLRP3炎性小体激活如何促进GA的发病机制，并开发新的治疗策略：(1)生成已知AMD相关应激源的时空图，以及与GA和早期AMD眼睛病理位点相关的NLRP3炎性小体激活标志物；(2)破译已知ga相关应激激活炎性体的分子机制；(3)确定急性和慢性AMD动物模型中炎症小体机制及其效应通路的阻断是否抑制RPE变性。这些研究将阐明GA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，该提案与NEI视网膜疾病项目战略计划的年度目标一致。

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.