权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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），一种晚期形式的老年性黄斑变性（AMD），是一个主要的全球原因