Role and regulation of inflammasome in the intraocular pressure-induced injury of retinal ganglion cells

炎症小体在眼压所致视网膜神经节细胞损伤中的作用及调控

• 批准号: 10389549
• 负责人: Markus Spurlock
• 金额: $ 4.68万
• 依托单位: UNIVERSITY OF MIAMI 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: 2022-01-10 至 2025-01-09
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10389549
• 关键词: Ablation; Acute; Affect; Angle-Closure Glaucoma; Antigen-Antibody Complex; Apoptosis; Axon; Blindness; Blood Pressure; CASP1 gene; Caffeine; Calcium; Calcium Channel; Cell Death; Cell Density; Cell Separation; Cell Survival; Cell physiology; Cell surface; Cessation of life; Chronic; Clinical; Clinical Treatment; Complex; Data; Disease; Electrophysiology (science); Electroretinography; Environmental Wind; Event; Exercise; Exposure to; Eye; Functional disorder; Genes; Genetic; Glaucoma; Head; Human; Inflammasome; Inflammatory; Injury; Intake; Interleukin-1; Intervention; Knockout Mice; Knowledge; Life Style; Link; Mechanical Stress; Mechanoreceptors; Metabolic stress; Modality; Modeling; Molecular; Mus; Neuronal Dysfunction; Neuronal Injury; Neurons; Ocular Hypertension; Operative Surgical Procedures; Oxidative Stress; Pathology; Pathway interactions; Pattern; Persons; Pharmaceutical Preparations; Pharmacology; Physiologic Intraocular Pressure; Play; Proteins; Receptor Signaling; Regulation; Research; Retinal Ganglion Cells; Risk Factors; Rodent; Role; Signal Pathway; Signal Transduction; Stress; Stroke; Surface; TRPV channel; Testing; Time; VDAC1 gene; Vision; Weight Lifting; Wild Type Mouse; acute stress; base; cell injury; cytokine; endoplasmic reticulum stress; improved; insight; instrument; ischemic injury; mouse model; neuroinflammation; neurotoxic; novel; pressure; receptor; response; retinal damage; retinal ganglion cell degeneration; sensor; Ablation; Acute; Affect; Angle-Closure Glaucoma; Antigen-Antibody Complex; Apoptosis; Axon; Blindness; Blood Pressure; CASP1 gene; Caffeine; Calcium; Calcium Channel; Cell Death; Cell Density; Cell Separation; Cell Survival; Cell physiology; Cell surface; Cessation of life; Chronic; Clinical; Clinical Treatment; Complex; Data; Disease; Electrophysiology (science); Electroretinography; Environmental Wind; Event; Exercise; Exposure to; Eye; Functional disorder; Genes; Genetic; Glaucoma; Head; Human; Inflammasome; Inflammatory; Injury; Intake; Interleukin-1; Intervention; Knockout Mice; Knowledge; Life Style; Link; Mechanical Stress; Mechanoreceptors; Metabolic stress; Modality; Modeling; Molecular; Mus; Neuronal Dysfunction; Neuronal Injury; Neurons; Ocular Hypertension; Operative Surgical Procedures; Oxidative Stress; Pathology; Pathway interactions; Pattern; Persons; Pharmaceutical Preparations; Pharmacology; Physiologic Intraocular Pressure; Play; Proteins; Receptor Signaling; Regulation; Research; Retinal Ganglion Cells; Risk Factors; Rodent; Role; Signal Pathway; Signal Transduction; Stress; Stroke; Surface; TRPV channel; Testing; Time; VDAC1 gene; Vision; Weight Lifting; Wild Type Mouse; acute stress; base; cell injury; cytokine; endoplasmic reticulum stress; improved; insight; instrument; ischemic injury; mouse model; neuroinflammation; neurotoxic; novel; pressure; receptor; response; retinal damage; retinal ganglion cell degeneration; sensor

PROJECT SUMMARY Glaucoma is the second leading cause of blindness, impacting 79.6 million worldwide 1. This blindness results from the loss of retinal ganglion cells (RGCs) and is primarily linked to chronic ocular hypertension (OHT). Because of gaps in our understanding of the molecular pathways linking OHT with RGC loss, the only current clinical strategy to slow glaucoma progression is to lower intraocular pressure (IOP). This strategy has serious limitations as it does not stop the disease and has a high proportion of non-responders 2. Elevation of IOP varies in magnitude and disrupts RGCs in several ways. High elevation (above systolic blood pressure) causes an acute and severe ischemic injury in these neurons, more common in closed-angle glaucoma, while lower magnitude chronic IOP elevations affect them slowly over time. Acute ischemic injury is similar to a stroke that activates pressure-sensitive calcium channels, induces oxidative and ER stresses, ATP release via activated Panx1/Cx hemichannels, and obstructs axonal transport3. More recent studies have revealed that the activation of the endogenous inflammasome and subsequent formation of GasderminD pores is a primary mechanism in neuronal dysfunction and pyroptotic death in ischemic OHT injury models 4, 5. In contrast, episodes of sub-ischemic low level but chronic IOP elevations can cause glaucoma despite being non- injurious short term6. In addition to these two modalities, rapid IOP elevation “spikes” below ischemic levels have been shown to induce RGC dysfunction and glaucomatous degeneration in both human and rodent eyes7, 8. In people, such pressure spikes can be induced by surgery and drugs and by activities such as eye rubbing, playing wind instruments, head down exercising, heavy weight lifting, and frequent caffeine intake, which have been linked to higher glaucoma risk2. However, the mechanisms causing RGC injury by such relatively low amplitude but rapid and recurring spiking IOP fluctuations are poorly understood. In this project, I utilize a model of sub-ischemic OHT spikes (SIOHS) to investigate early RGC-damaging pathways and their role in glaucomatous RGC degeneration. My main focus is on the mechanism linking mild acute stress by sub-ischemic OHT spikes with the functional deficit and RGC loss. In this project, I will test the hypothesis that overactivation of mechanosensitive channels on the cell surface of RGCs challenged by IOP spikes initiates metabolic stress and eventual loss via the activity of endogenous inflammasome. To examine this, I will determine 1. the role of endogenous neuroinflammation in RGC dysfunction and death following SIOHS, and 2. Test if cell surface TLRPV4 receptor signaling pathway is specifically responsive to SIOHS events.

项目摘要 青光眼是失明的第二大主要原因，在全球范围内影响7960万。 从残留神经节细胞（RGC）的丧失中，主要与慢性眼高血压（OHT）有关。 由于我们对将OHT与RGC损失联系起来的分子途径的理解差距，这是唯一的电流 缓慢青光眼进展的临床策略是降低眼内压（IOP）。这个策略很严重 局限性不会阻止疾病，并且没有比例很高的非反应者2。 IOP的高度在大小上，并以多种方式破坏RGC。高海拔（收缩血上方 压力）在这些神经元中引起急性和严重的缺血性损伤，在闭合角度更常见 青光眼，而较低的慢性IOP升高会随着时间的流逝而缓慢地影响它们。急性缺血性损伤是 类似于激活压力敏感钙通道的中风，诱导氧化和ER应力，ATP 通过激活的panx1/cx半通道释放，并阻塞轴突运输3。最近的研究已经 揭示了内源性炎症体的激活和随后的气囊形成 是缺血性OHT损伤模型4、5的神经元功能障碍和凋亡死亡的主要机制。 对比，低缺血水平的发作，但慢性IOP升高可能导致青光眼目的地是非 - 有害短期6。除了这两种方式外，低于缺血水平的快速IOP高程还具有 被证明会诱导人和啮齿动物眼中的RGC功能障碍和青光眼变性7，8。 人们可以通过手术和药物以及诸如眼睛摩擦，玩耍等活动来诱发这种压力尖峰 风乐器，锻炼头​​，重量举重以及经常是咖啡因摄入量 与较高的青光眼风险有关。但是，这种机制导致这种相对较低的放大器造成RGC损伤 但是，众所周知，快速而反复出现的尖峰IOP波动知之甚少。 在这个项目中，我利用了一个次缺血的OHT尖峰模型（SIOHS）来研究早期RGC损害 途径及其在青光眼RGC变性中的作用。我的主要重点是连接中间的机制 急性应激由功能不足和RGC损失带来的下降OHT尖峰。在这个项目中，我将测试 假设IOP挑战的RGC细胞表面上的机械敏感通道过度活化 尖峰通过内源性炎症体的活性引发了代谢应力和最终丧失。 为了检查这一点，我将确定1。内源性神经炎症在RGC功能障碍和死亡中的作用 遵循SIOHS和2。测试细胞表面TLRPV4接收器信号通路是否特别响应 SIOHS事件。