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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要青光眼是导致失明的第二大原因，影响全球 7,960 万人1。这种失明会导致视网膜神经节细胞 (RGC) 损失所致，主要与慢性高眼压 (OHT) 有关。由于我们对 OHT 与 RGC 损失之间的分子途径的理解存在差距，目前唯一的研究减缓青光眼进展的临床策略是降低眼内压（IOP），这种策略具有严重的后果。局限性，因为它不能阻止疾病，并且无反应者比例很高 2。眼压升高的幅度各不相同，并以多种方式破坏 RGC。高眼压（高于收缩压）。压力）会导致这些神经元发生急性和严重的缺血性损伤，在闭角型疾病中更常见青光眼，而较低程度的慢性眼压升高会随着时间的推移缓慢地影响它们。类似于中风，激活压力敏感钙通道，诱导氧化和内质网应激，ATP 最近的研究表明，通过激活的 Panx1/Cx 半通道释放，并阻碍轴突运输。揭示了内源性炎症小体的激活以及随后 GasderminD 孔的形成是缺血性 OHT 损伤模型中神经元功能障碍和焦亡的主要机制 4, 5。相比之下，亚缺血性低水平但慢性眼压升高的发作可导致青光眼，尽管不是除了这两种方式外，眼压快速升高至低于缺血水平也有损害。已被证明会引起人类和啮齿动物眼睛的 RGC 功能障碍和青光眼变性7, 8。人们，这种压力峰值可能是由手术、药物以及揉眼、玩耍等活动引起的管乐器、低头运动、举重以及经常摄入咖啡因，这些都是与较高的青光眼风险相关2 然而，这种相对较低的幅度导致 RGC 损伤的机制。但人们对快速且反复出现的眼压波动知之甚少。在这个项目中，我利用亚缺血性 OHT 尖峰 (SIOHS) 模型来研究早期 RGC 损伤我主要关注的是与轻度 RGC 变性相关的机制。亚缺血性 OHT 引起的急性应激伴随功能缺陷和 RGC 损失。假设 RGC 细胞表面的机械敏感通道受到 IOP 的挑战峰值通过内源性炎症小体的活动引发代谢应激并最终损失。为了验证这一点，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，以及 2. 测试细胞表面 TLRPV4 受体信号通路是否对 SIOHS 活动。