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：
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
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/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&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 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

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.

项目摘要/摘要机械敏感的离子通道显示在中央驱动机械诱导的炎症信号传导以及神经病，骨骼疾病，创伤性大脑的外周神经系统和加剧病理损伤和其他神经退行性条件。通过基因敲低和药理学减少了炎症性神经病和神经元损伤神经炎症几乎没有理解，它们对与压力相关的残留疾病（例如青光眼从未被研究过。拟议项目的目的是解决这一主要差距通过定义主要残留大分子中的眼内压的分子靶标的知识细胞，并建立Müller压力感应在神经炎症，神经胶质 - 神经元相互作用的重要性和神经变性。该项目的总体假设是机械敏感的TRP和压电通道触发并驱动在存在机械应力源（例如眼压和应变）的情况下，炎症激活该过程可以通过药物/遗传方法来减轻神经元损伤。我们将解决这两个特定目标中的假设。 AIM 1专注于机械激活特性的表征离子通道介导müller细胞中的压力信号传导。在AIM 2中，我们建议利用新的优势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病，神经胶质和神经胶质神经元电路的机械转导，以及该机制对神经节细胞的重要性压力和生存。这些多学科的，主题相关但独立的成功完成方法可能有助于定义高血压青光眼的新诊断和治疗策略。