Inflammasome Activation in Geographic Atrophy

描述（申请人提供）：地图状萎缩（GA）是一种无法治疗的晚期年龄相关性黄斑变性（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阻碍了FDA批准的任何治疗方法的发展，这些治疗方法用于100万被诊断患有GA的美国人和数百万有发展GA风险的人。在新的和令人兴奋的研究中，我们发现了在具有GA的人眼的RPE中NLRP 3炎性体复合物的非常规免疫激活（Tarallo等人，Cell 2012），其响应于在RNase DICER 1缺陷期间毒性非编码Alu RNA的特异性积累而发生，并诱导RPE变性（Kaneko等人，Nature 2011）。非免疫细胞中病理性炎性小体激活的这一令人惊讶的发现是理解GA发病机制和阐明决定视网膜活力的基本效应子途径的关键步骤。我们的发现引入了自身免疫的新定义：响应于自身衍生的Alu RNA的NLRP 3炎性小体的RPE活化代表了对内源性炎性小体活化的第一次描述，同时在经典免疫特权的眼部环境中引起病理学。重要的是，沿着NLRP 3炎性体激活的多个分子步骤的阻断阻断了RPE细胞死亡，从而提供了一种重要的基于机制的策略来减轻GA的全球负担。然而，我们仍然缺乏对其他AMD相关应激源是否也引起GA中炎性小体激活的综合理解，如果是这样，这些机制如何精确地聚集在诱导RPE变性的共同效应子途径上。这些机制的严格定义对于增强我们对GA分子驱动因素的理解和开发合理的治疗方法至关重要。我们将提供关于NLRP 3炎性小体激活失调如何有助于GA发病机制的新的功能性见解，并通过以下目的开发新的治疗策略：（1）产生已知的AMD相关应激源和NLRP 3炎性小体激活标记物与GA和早期AMD眼睛中的病理位点相关的时空图;（2）通过已知的GA相关应激来解读炎性小体激活的分子机制;（3）确定在AMD的急性和慢性动物模型中阻断炎性小体机制及其效应物通路是否抑制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，这项建议与NEI的视网膜疾病计划战略计划的年目标是一致的。

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.