Non-canonical inflammasome in activation in RPE degeneration

RPE 变性中激活的非典型炎症小体

基本信息

批准号：
10338080
负责人：
Jayakrishna Ambati
金额：
$ 56.4万
依托单位：
UNIVERSITY OF VIRGINIA
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-02-01 至 2024-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10338080
关键词：
Acute Affect Age related macular degeneration American Amyloid beta-Protein Anatomy Animal Model Animals Antibodies Apoptosis Basal lamina Biochemical Biological Models Blindness Bruch&apos s basal membrane structure CASP1 gene Caspase Cell Culture Techniques Cell Death Characteristics Cholesterol Choroidal Neovascularization Chronic Clinical Trials Complex Cytosol DICER1 gene Data Deposition Disease Distress Dropout Drusen Exhibits Eye FDA approved Fatty acid glycerol esters Foundations Functional disorder Genetic Goals Histologic Human Immune Inflammasome Interferon-beta Interleukin-1 beta Interleukin-18 Lipids Lytic Maps Mediating Medical Medicine Mitochondrial DNA Modeling Molecular Molecular Target Mus Nature Nonlytic Pathologic Pathology Pathway interactions Pharmacology Photoreceptors Publishing RNA Regulation Retina Retinal Degeneration Retinal Diseases Role Severities Signal Transduction Strategic Planning Structure of retinal pigment epithelium System Testing Therapeutic Toxic effect Translating Untranslated RNA Vision research apolipoprotein E-4 base clinical biomarkers cytokine extracellular genetic epidemiology geographic atrophy human disease insight mouse model novel novel therapeutics programs scaffold

项目摘要

Geographic atrophy (GA), an advanced form of age-related macular degeneration (AMD), is a major global cause of blindness that affects more than 1 million Americans. Of the many pathological features that comprise GA, one of the cardinal hallmarks is degeneration of the retinal pigmented epithelium (RPE), which also is an FDA- accepted endpoint for registration clinical trials. GA remains an unmet medical need because, in large part, the mechanisms that promote RPE degeneration are not fully resolved. Earlier, we identified a specific accumulation of toxic non-coding Alu RNAs in the RPE of GA eyes that results from a deficiency in DICER1 (Nature 2011), which triggers RPE degeneration by activating the canonical caspase-1 inflammasome (Cell 2012). Recently, we elucidated the signaling symphony that orchestrates this cellular toxicity: disruption of DICER1:Alu RNA homeostatic regulation induces non-canonical inflammasome activation, a molecular cascade mediated by caspase-4/11 and a novel, non-lytic gasdermin D (GSDMD)- dependent activation of caspase-1 and secretion of IL-18 (Nature Medicine 2018). Enhanced levels of these molecules were also identified in human GA, marking it as the first non-infectious human disease associated with the non-canonical inflammasome. Combined with our exciting preliminary data that amyloid β, another trigger of RPE degeneration, also activates the non-canonical inflammasome, these findings suggest that the non-canonical inflammasome could be an integrator of multiple toxic signals that drive RPE degeneration in GA. Given that the inflammasome responds to myriad triggers of cellular distress, it could represent a critical checkpoint that triggers cell death, and therefore an attractive target for halting RPE degeneration. However, we still lack an integrated understanding of inflammasome activation in GA, and how it induces RPE degeneration. A rigorous definition of these mechanisms is crucial to enhancing our understanding of the molecular drivers of this hallmark of GA and to developing rational treatments. We will provide novel functional insights into how dysregulated non-canonical inflammasome activation contributes to RPE degeneration via the following thematically integrated yet independent Aims: (1) Create a spatial map of the non-canonical inflammasome pathway in human donor eyes; (2) Define the role of Gasdermin D (GSDMD) in non-canonical inflammasome activation; (3) Determine whether targeting the non-canonical inflammasome pathway ameliorates RPE degeneration in acute and chronic animal models. These studies will illuminate novel aspects of the molecular and biochemical bases of RPE degeneration, and help validate a molecular targeting strategy that could be translated into clinical trials. As such, this proposal is aligned with the 5-year goals of the NEI's Retinal Diseases Program strategic plan.

地理萎缩 (GA) 是年龄相关性黄斑变性 (AMD) 的一种高级形式，是全球的一个主要原因影响超过 100 万美国人的失明在构成 GA 的众多病理特征中，主要标志之一是视网膜色素上皮 (RPE) 变性，这也是 FDA- 注册临床试验的公认终点仍然是一个未满足的医疗需求，因为在很大程度上，促进 RPE 退化的机制尚未完全解决。早些时候，我们发现了 GA 眼 RPE 中有毒非编码 Alu RNA 的特定积累，导致来自 DICER1 缺陷（Nature 2011），它通过激活典型的 RPE 信号来触发 RPE 退化。 caspase-1 炎症小体 (Cell 2012) 最近，我们阐明了协调这一过程的信号交响曲。细胞毒性：DICER1:Alu RNA 稳态调节的破坏诱导非典型炎症小体激活，由 caspase-4/11 和新型非裂解性 Gasdermin D (GSDMD) 介导的分子级联 - caspase-1 的依赖性激活和 IL-18 的分泌（Nature Medicine 2018）。人类 GA 中也发现了这些分子，这标志着它成为第一个与非传染性人类疾病相关的分子。结合我们令人兴奋的初步数据，β淀粉样蛋白，另一个。 RPE 变性的触发因素，也会激活非典型炎症小体，这些发现表明非典型炎症小体可能是驱动 GA 中 RPE 变性的多种毒性信号的整合者。鉴于炎症小体对细胞应激的无数触发因素做出反应，它可能代表了一个关键的因素。触发细胞死亡的检查点，因此是阻止 RPE 退化的有吸引力的目标。仍然缺乏对 GA 中炎症小体激活及其如何诱导 RPE 变性的全面了解。这些机制的严格定义对于增强我们对分子驱动因素的理解至关重要遗传算法的这一特点以及开发合理的治疗方法我们将提供新颖的功能见解。失调的非典型炎症小体激活通过以下方式导致 RPE 变性主题上整合但独立的目标：（1）创建非规范炎症体的空间图 (2) 定义 Gasdermin D (GSDMD) 在非典型炎症体中的作用 (3) 确定靶向非典型炎症小体通路是否可以改善 RPE 这些研究将阐明急性和慢性动物模型的变性。和 RPE 变性的生化基础，并帮助验证可能的分子靶向策略因此，该提案与 NEI 视网膜疾病的 5 年目标一致。制定战略计划。