The Role of Pannexin 1 Pathway in Ocular Hypertension Injury of Retinal Ganglion Cells

Pannexin 1通路在高眼压视网膜神经节细胞损伤中的作用

• 批准号: 10253224
• 负责人: VALERY I SHESTOPALOV
• 金额: $ 12.44万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-01 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10253224
• 关键词: Ablation; Acute; Affect; Animal Model; Apoptotic; Astrocytes; Axon; Biology; Blindness; CASP1 gene; CASP3 gene; Caspase; Cell Death; Chronic; Clinical; Complex; Connexin 43; Development; Disease; Drug Design; Drug Targeting; Environment; Event; Experimental Animal Model; Eye; Family; Functional disorder; Genetic Transcription; Glaucoma; Goals; Human; IL18 gene; Inflammasome; Inflammation; Inflammatory; Injury; Interleukin-1; Interleukin-1 beta; Knowledge; Link; Mechanical Stress; Mechanics; Mediating; Modeling; Molecular; Multiprotein Complexes; Mus; NF-kappa B; Nerve Degeneration; Neurodegenerative Disorders; Neuroglia; Neuronal Injury; Neurons; Ocular Hypertension; Optic Nerve; Outcome Study; P2X-receptor; Pathologic; Pathology; Pathway interactions; Peptide Hydrolases; Physiologic Intraocular Pressure; Production; Proteins; Regulation; Research; Research Project Grants; Retina; Retinal Ganglion Cells; Risk Factors; Role; Signal Pathway; Signal Transduction; Testing; Therapeutic; Toxic effect; Tumor Necrosis Factor Receptor; United States National Institutes of Health; base; cytokine; design; drug development; extracellular; improved; insight; ischemic injury; knowledge base; neuroinflammation; neuron loss; neurotoxic; neurotoxicity; neurotransmission; novel; novel strategies; novel therapeutic intervention; prevent; receptor; response; therapeutic target

Abstract Elevated IOP is the major risk factor in glaucoma, a neurodegenerative disorder affecting 80 million people worldwide. Loss of retinal ganglion cells and their axons is the major pathological hallmark of glaucoma, the disease facilitated by mechanical damage neuroinflammation and danger signaling. These pathological factors were identified in human glaucoma and in experimental animal models. Our long-term goal is to decrease and, ultimately, prevent vision loss in glaucoma and other retinal and optic nerve pathologies induced by intraocular pressure. Pursuant to our objective, we will characterize a novel pathway that facilitates RGC dysfunction and loss via an interaction between P2X receptors, pannexin1 (Panx1), and inflammasome in the retina. Our project is premised on our preliminary studies that identified two new Panx1 partners that may contribute to RGC toxicity, including upstream regulator P2RX4 and a downstream target, the inflammasome. We found that this signaling cascade activates caspase 1 and 11, the core inflammasome proteases. We will, therefore, test our central hypothesis that the activation of neuronal P2(R)X4 is pivotal for Panx1-mediated neurotoxicity, which triggers inflammasome activation in response to elevated intraocular pressure. Our three specific aims are designed to test this hypothesis and determine whether retinal inflammasome is critical for RGC dysfunction or loss. Specific Aims are designed to: 1) Establish the role of P2X4 receptor in Panx1-mediated loss of RGCs and their axons; 2) Examine the mechanism of P2(R)X4 regulation of Panx1, caspases and the inflammasome, and 3) Determine whether glial ATP release facilitate neuronal inflammasome activation and contribute to Panx1- mediated RGC loss. Significance. This project has a translational potential and is significant because it is developing and testing a novel strategy against inflammation-induced neurodegeneration, implicated in glaucoma, a clinical problem identified by the NIH as a crucial research objective. Preventing vision loss in major blinding pathologies like glaucoma and other ischemic injuries of retina require a comprehensive, knowledge-based therapeutic strategy. This proposal is designed to provide mechanistic understanding for the role of newly discovered non- canonical inflammasome pathway in animal models for these pathologies. This research project will establish the role and feasibility of therapeutic targeting of Panx1-P2X and inflammasome pathways in the chronic ocular hypertension models, relevant to glaucomatous pathology. If successful, the new knowledge of basic biology of inflammation-induced neuronal damage in the retina will help us to identify new targets for rational drug design.

摘要 眼压升高是青光眼的主要危险因素，青光眼是一种影响8000万人的神经退行性疾病 国际吧视网膜神经节细胞及其轴突的丧失是青光眼的主要病理标志， 疾病由机械损伤、神经炎症和危险信号促进。这些病理因素 在人类青光眼和实验动物模型中被鉴定。我们的长期目标是减少， 最终，预防青光眼和其他视网膜和视神经病变引起的视力丧失， 压力根据我们的目标，我们将描述一种促进RGC功能障碍的新途径， 通过视网膜中P2 X受体、pannexin 1（Panx 1）和炎性小体之间的相互作用而导致的损失。我们 该项目是基于我们的初步研究，确定了两个新的Panx 1合作伙伴，可能有助于 RGC毒性，包括上游调节因子P2 RX 4和下游靶标炎性体。我们发现 这种信号级联激活了caspase 1和11，这两种核心炎性蛋白酶。因此，我们将， 测试我们的中心假设，即神经元P2（R）X4的激活是Panx 1介导的神经毒性的关键， 其响应于升高的眼内压而触发炎性小体活化。三个具体目标 旨在验证这一假设，并确定视网膜炎性小体是否是RGC的关键 功能障碍或丧失。 具体目的设计为：1）建立P2 X4受体在Panx 1介导的RGC损失中的作用， 2）研究P2（R）X4对Panx 1、半胱天冬酶和炎性小体的调节机制， 3)确定神经胶质ATP释放是否促进神经元炎性小体激活并促进Panx 1 - 1表达。 介导的RGC丢失。 意义该项目具有转化潜力，意义重大，因为它正在开发和测试一个 一种新的对抗炎症诱导的神经变性的策略，涉及青光眼，一个临床问题 被美国国立卫生研究院确定为重要的研究目标。预防主要致盲疾病中的视力丧失， 青光眼和其他视网膜缺血性损伤需要全面的、基于知识的治疗方法 战略该建议旨在为新发现的非- 在这些病理学的动物模型中的典型炎性体途径。该研究项目将建立 Panx 1-P2 X和炎性体通路在慢性眼部疾病中的作用和可行性 高血压模型，与高血压昏迷病理学相关。如果成功的话， 炎症诱导的视网膜神经元损伤将帮助我们确定合理药物设计的新靶点。