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

项目概要/摘要 机械敏感离子通道被证明可以驱动中枢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。

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.