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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

基本信息

批准号：
10219761
负责人：
DAVID KRIZAJ
金额：
$ 39.66万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
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/10219761
关键词：
Ablation Address Astrocytes Automobile Driving Biological Assay Biomechanics Blindness Calcium Calcium Signaling Cell Survival Cell model Cell physiology Cells Cellular Stress 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 Methods Microglia Molecular Molecular Target Muller&apos 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 Plant Roots 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 base calcium indicator cell injury cell water chemokine conditional knockout cytokine experimental study ganglion cell gene gun inhibitor/antagonist innovation knock-down luciferin macroglia mechanical drive mechanotransduction mouse model multidisciplinary neuroinflammation neuronal circuitry neuroprotection normotensive novel diagnostics pressure prevent receptor response retinal axon retinal ganglion cell degeneration skeletal disorder small hairpin RNA stressor treatment strategy two photon microscopy

项目摘要

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.

项目总结/摘要机械敏感性离子通道显示驱动中枢神经系统中机械诱导的炎症信号传导。和周围神经系统，并加重神经病、骨骼疾病、创伤性脑损伤和其他神经变性病症。通过基因敲除抑制它们的激活，药理学可减少炎性神经病变和神经元损伤，但尽管有这些知识，神经炎症是很少了解，和他们的贡献，压力相关的视网膜疾病，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中眼内压的分子靶点，Müller 细胞，并建立神经炎症，神经胶质-神经元相互作用的Müller压力传感的意义和神经退化该项目的总体假设是，机械敏感TRP和压电通道触发并驱动在机械应激源如眼内压和应变存在下的炎性激活，可以通过药理学/遗传学方法靶向该过程以减轻神经元损伤。我们将解决这一假设有两个具体目标。目的1着重于表征机械活化的 Müller细胞中介导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，以阐明压力升高如何诱导反应性神经胶质增生，神经胶质-神经胶质和神经胶质-神经元回路中的机械传递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、主题相关但独立的这些方法可能有助于确定高血压性青光眼的新诊断和治疗策略。