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

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.

项目总结