Cellular and Molecular Mechanisms that Contribute to Pressure-Induced Retinal Inflammation and Pathology

导致压力引起的视网膜炎症和病理学的细胞和分子机制

• 批准号: 10656446
• 负责人: DAVID KRIZAJ
• 金额: $ 38.35万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10656446
• 关键词: Ablation; Astrocytes; Automobile Driving; Biological Assay; Biomechanics; Blindness; Calcium; Calcium Signaling; Cell Survival; Cell model; Cell physiology; Cells; Cellular Stress; Central Nervous System; Chronic; Closure by clamp; Dendrites; Early Diagnosis; Early treatment; Electrophysiology (science); Family; Generations; Genes; Genetic; Glaucoma; Gliosis; Goals; Homeostasis; Hypertrophy; Image; Immunophenotyping; In Vitro; Inflammation; Inflammatory; Injury; Intervention; Ion Channel; Ions; Knockout Mice; Knowledge; Lead; Link; Luciferases; Mechanical Stress; Mechanics; Mediating; Membrane; Methods; Microglia; Molecular; Molecular Target; Muller' s cell; Nerve Degeneration; Neuroglia; Neuronal Injury; Neurons; Neuropathy; Pathologic; Pathology; Pathway interactions; Peripheral Nervous System; Permeability; Pharmacology; Physiologic Intraocular Pressure; Piezo 1 ion channel; Piezo ion channels; Process; Property; RNA; Regulation; Research; Retina; Retinal Diseases; Retinal Ganglion Cells; Role; Signal Transduction; Speed; Stress; Stretching; Swelling; Synapses; TRP channel; Testing; Tissues; Transcript; Transfection; Transgenic Organisms; Traumatic Brain Injury; Vanilloid; Work; axon injury; calcium indicator; cell injury; cell water; chemokine; conditional knockout; cytokine; diagnostic strategy; experimental study; ganglion cell; gene gun; hypertensive; inhibitor; innovation; knock-down; luciferin; macroglia; mechanical drive; mechanotransduction; mouse model; multidisciplinary; neuroinflammation; neuronal circuitry; neuroprotection; neurotransmission; normotensive; novel diagnostics; pharmacologic; pressure; prevent; receptor; response; retinal ganglion cell degeneration; skeletal disorder; small hairpin RNA; stressor; treatment strategy; two photon microscopy

PROJECT SUMMARY/ABSTRACT Mechanosensitive ion channels were shown to drive mechanically induced inflammatory signaling in the central and peripheral nervous systems and to exacerbate pathology in neuropathies, skeletal diseases, traumatic brain injury and other neurodegenerative conditions. Suppressing their activation with gene knockdown and pharmacology reduces inflammatory neuropathy and neuronal injury yet despite this knowledge their role in neuroinflammation is little understood, and their contribution to pressure-associated retinal diseases such as glaucoma has never been investigated. The goal of the proposed project is to resolve this major gap in knowledge by defining the molecular targets of intraocular pressure in the principal retinal macroglia, the Müller cell, and establish the significance of Müller pressure sensing for neuroinflammation, glia-neuronal interactions and neurodegeneration. The overall hypothesis of this project is that mechanosensitive TRP and piezo channels trigger and drive inflammatory activation in the presence of mechanical stressors such as intraocular pressure and strain and that this process can be targeted by pharmacological/genetic methods to alleviate neuronal injury. We will address this hypothesis in two specific aims. Aim 1 focuses on the characterization of properties of mechanoactivated ion channels that mediate pressure signaling in Müller cells. In Aim 2 we propose to take advantage of new conditional mouse models to elucidate how pressure elevations induce reactive gliosis, the role of mechanotransduction in glia-glia and glia-neuronal circuits, and significance of this mechanism for ganglion cell stress and survival. Successful completion of these multidisciplinary, thematically related yet independent approaches may help define new diagnostic and treatment strategies in hypertensive glaucoma.

项目摘要/摘要 机械敏感离子通道被证明驱动机械诱导的中枢炎症信号。 和周围神经系统，并加剧神经病、骨骼疾病、创伤性脑损伤的病理 损伤和其他神经退行性疾病。通过基因敲除来抑制它们的激活 药物可以减少炎症性神经病变和神经元损伤，尽管如此，它们在 神经炎症知之甚少，它们在压力相关视网膜疾病中的作用 青光眼从未被研究过。拟议项目的目标是解决这一重大差距 通过定义主要视网膜大胶质细胞Müler眼压的分子靶点来认识 建立了Müler压力传感在神经炎症、神经胶质细胞-神经元相互作用中的意义 和神经退化。 这个项目的总体假设是机械敏感的色氨酸和压电通道触发和驱动 在机械应激源存在时的炎症激活，如眼压和应变，以及 这一过程可以通过药理学/遗传学方法进行靶向治疗，以减轻神经元损伤。我们将解决 这一假设有两个具体目的。目的1着重于机械活化的性质的表征 在米勒细胞中调节压力信号的离子通道。在目标2中，我们建议利用新的 有条件的小鼠模型阐明压力升高如何诱导反应性胶质细胞增生，其作用 神经胶质细胞和神经胶质细胞环路中的机械转导及其对神经节细胞的意义 压力和生存。成功完成这些多学科、主题相关但独立的课程 方法可能有助于确定高血压青光眼的新诊断和治疗策略。