Neurotoxicity of Reactive Astrocyte-secreted Lipids in Neurodegenerative Disease

反应性星形胶质细胞分泌的脂质在神经退行性疾病中的神经毒性

• 批准号: 10342373
• 负责人: Shane Liddelow
• 金额: $ 46.78万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-01 至 2026-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10342373
• 关键词: Acute; Address; Affect; Aging; Apoptosis; Astrocytes; Automobile Driving; Autopsy; Axon; BBC3 gene; Blindness; CASP3 gene; CRISPR screen; Cell Death; Cells; Cessation of life; Characteristics; Chronic; Development; Disease; Electrophysiology (science); Enzymes; Excision; Eye; Eye Injuries; Eye diseases; Future; Genetic; Glaucoma; Goals; Health; Human; Immune response; In Vitro; Individual; Infection; Inflammation; Injury; Knock-out; Knockout Mice; Lipids; Maintenance; Maps; Mediating; Mediator of activation protein; Modeling; Mus; Nerve Crush; Nerve Degeneration; Neuraxis; Neurodegenerative Disorders; Neurons; Neurotoxins; Nonesterified Fatty Acids; Optic Nerve; Optic Nerve Injuries; Pathologic; Pathway interactions; Patients; Peripheral; Pharmacology; Phenotype; Phosphotransferases; Physiologic Intraocular Pressure; Physiological; Predisposition; Production; Proteins; Puma; Reporting; Research; Resistance; Retina; Retinal Degeneration; Retinal Ganglion Cells; Rodent Model; Role; Stress; Synapses; Testing; Thalamic structure; Time; Tissues; Toxic effect; Vision; Visual Acuity; Western Blotting; Work; activating transcription factor 3; axon injury; biological adaptation to stress; cell type; combinatorial; endoplasmic reticulum stress; improved; in vivo; in vivo Model; innovation; insight; ischemic injury; knockout animal; mouse model; neuron loss; neuronal cell body; neurotoxic; neurotoxicity; neurotransmission; neurotrophic factor; new therapeutic target; novel; novel strategies; preservation; prevent; protein kinase R; regeneration following injury; response to injury; saturated fat; tool; virtual reality system

PROJECT SUMMARY Glaucoma is a neurodegenerative disease of aging that features the death of retinal ganglion cell neurons (RGCs) in the retina, often as a result of prolonged increases in intraocular pressure. This cell death leads to a decrease in visual acuity and ultimately blindness. While glial and immune responses have been associated with glaucoma, little understood about their potential causative role in loss of vision. Reactive astrocytes are increasingly shown to appear well before traditional pathological readouts of a wide range of neurodegenerative diseases, including glaucoma. One subset of reactive astrocytes reported by us and others as putatively neurotoxic. These neurotoxic reactive astrocytes are present in regions of neurodegeneration in human postmortem tissue from patients with multiple diseases of aging, as well as in the retina following acute injury to RGC axons and in a chronic retinal degeneration in a bead occlusion model of glaucoma. Preventing formation of neurotoxic reactive astrocytes prevents death of neurons, and spared neurons are electrophysiologically functional and thus still have potential value for regeneration following injury and in disease. We now report that these reactive astrocytes secrete a potent neurotoxic lipid, specifically long-chain free fatty acids, that induce death of neurons, both in vitro and in vivo. Block of the enzyme involved in production of toxic lipids, Elovl1, in astrocytes preserves neuron numbers. Together, these findings highlight a subset of reactive astrocytes as drivers of RGC death in a chronic neurodegenerative disease of the eye. Here we will investigate the role of reactive astrocyte-derived toxic lipids to determine the timing and mechanism of reactive astrocytes in driving death of RGC somas in the retina, during acute and chronic injury to the eye. We will focus on three broad research questions: is the PERK-ATF3 pathway required to drive neuron cell death by astrocyte toxic lipids? Does blocking neurotoxic reactive astrocytes preserve neuronal function and visual acuity in a mouse model of glaucoma? And what is the requirement for neuronal susceptibility prior to astrocyte-induced cell death? We will determine maintenance of optic nerve axons using a mouse model deficient for neurotoxic lipids released by reactive astrocytes in combination with investigating changes in visual acuity in glaucomatous mice using both wildtype and toxic lipid-deficient mice to determine if targeting reactive astrocytes can preserve vision. We will also investigate individual components of the PERK-ATF3 mediated lipoapoptosis pathway – a putative mechanism by which reactive astrocyte secreted toxic lipids drive death of neurons. This proposal will investigate a novel approach to maintain vision during glaucoma. It will provide for the first time a connection between astrocyte reactivity, RGC health, visual acuity, and thalamic synaptic connections.

项目概要 青光眼是一种神经退行性疾病，其特征是视网膜神经节细胞神经元死亡 视网膜中的 RGC（RGC），通常是由于眼内压长期升高造成的。这种细胞死亡会导致 视力下降并最终失明。虽然神经胶质细胞和免疫反应与 青光眼，人们对其导致视力丧失的潜在致病作用知之甚少。反应性星形胶质细胞是 越来越多的证据表明，其出现早于各种神经退行性疾病的传统病理读数 疾病，包括青光眼。我们和其他人推测的反应性星形胶质细胞的一个子集 神经毒性。这些神经毒性反应性星形胶质细胞存在于人类神经变性区域 患有多种衰老疾病的患者的死后组织，以及急性损伤后的视网膜 RGC 轴突和青光眼珠闭塞模型中慢性视网膜变性。防止形成 神经毒性反应性星形胶质细胞可防止神经元死亡，而幸存的神经元在电生理学上 具有功能性，因此对于受伤和疾病后的再生仍然具有潜在价值。 我们现在报告说，这些反应性星形胶质细胞分泌一种有效的神经毒性脂质，特别是长链游离脂肪 酸，在体外和体内诱导神经元死亡。阻断参与有毒物质产生的酶 星形胶质细胞中的脂质 Elovl1 可以保留神经元数量。总之，这些发现突出了反应性的一个子集 星形胶质细胞作为眼睛慢性神经退行性疾病中 RGC 死亡的驱动因素。在这里我们将调查 反应性星形胶质细胞来源的有毒脂质在确定反应性星形胶质细胞的时间和机制中的作用 在眼睛急性和慢性损伤期间，驱动视网膜 RGC 细胞死亡。我们将重点关注三个方面 广泛的研究问题：星形胶质细胞驱动神经元细胞死亡是否需要 PERK-ATF3 途径 有毒脂质？阻断神经毒性反应性星形胶质细胞是否可以保护神经元功能和视力 在青光眼小鼠模型中？之前对神经元敏感性的要求是什么 星形胶质细胞诱导的细胞死亡？我们将使用小鼠模型确定视神经轴突的维护 缺乏反应性星形胶质细胞释放的神经毒性脂质，并结合研究视觉变化 使用野生型和有毒脂质缺乏小鼠来评估青光眼小鼠的敏锐度，以确定是否靶向反应性 星形胶质细胞可以保护视力。我们还将研究 PERK-ATF3 介导的各个成分 脂肪凋亡途径——反应性星形胶质细胞分泌有毒脂质驱动细胞死亡的一种推定机制 神经元。 该提案将研究一种在青光眼期间维持视力的新方法。它将首先提供 计算星形胶质细胞反应性、RGC 健康、视力和丘脑突触连接之间的联系。