The role of mechanosensation in the vertebrate retina

机械感觉在脊椎动物视网膜中的作用

• 批准号: 9388693
• 负责人: DAVID KRIZAJ
• 金额: $ 37.94万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-12-01 至 2018-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9388693
• 关键词: Acute; Address; Affect; Agonist; Architecture; Axon; Axonal Neuropathy; Axonal Transport; Behavioral; Biochemical Pathway; Biophysics; Calcium; Cell membrane; Cell physiology; Cells; Chemicals; Chronic; Cytoskeleton; Data; Dendrites; Dependence; Development; Diagnosis; Disease; Early Diagnosis; Environment; Extracellular Matrix; Eye; Gene Expression; Genetic; Glaucoma; Goals; Growth; Homeostasis; Inflammation; Inflammatory; Injury; Ion Channel; Ischemia; Knowledge; Light; Link; Lipids; Location; Maintenance; Mammalian Cell; Mechanical Stress; Mechanics; Mediating; Mediation; Modeling; Molecular; Muller' s cell; Mus; Mutation; Nerve Degeneration; Neuroglia; Neuronal Injury; Ocular Hypertension; Phenotype; Physiologic Intraocular Pressure; Physiological; Play; Predisposition; Pressure Transducers; Property; Protein Isoforms; Regulation; Research; Retina; Retinal; Retinal Diseases; Retinal Ganglion Cells; Risk Factors; Role; Severe dysplasia; Signal Transduction; Stimulus; Stretching; Subcellular structure; Swelling; Synapses; TRP channel; Temperature; Testing; Time; Transducers; Vision; Visual; Work; capsaicin receptor; cell injury; design; experimental study; glial activation; human disease; insight; mechanical force; mechanotransduction; neuronal cell body; novel; pressure; response; retinal axon; retinal neuron; sensor; synaptic function; tool

Retinal ganglion cells and Müller glia are particularly susceptible to mechanical forces which drive inflammatory activation and RGC degeneration in diseases such as glaucoma, but the pressure transduction mechanisms are not well understood. Earlier studies have been limited to phenotyping the genetic, molecular, cellular and behavioral consequences of RGC injury and glial activation induced by elevated pressure. While many biochemical pathways were shown to be altered in hypertensive eyes, the molecular sensors that transduce mechanical forces remain obscure, confounding interpretations of time-dependence of pressure-induced remodeling changes within the retina. The dominant hypotheses about pressure injury in glaucoma focus on the role of forces on the stretch of the lamina cribrosa yet mice develop the disease but do not have the collagenous lamina. The axocentric hypotheses also cannot explain how mild pressure elevations induce early changes in dendritic architecture and synaptic function, or activate glia without visible changes in axonal transport. It is also not known how physiological levels of intraocular pressure might inform RGC physiology and whether they are sufficient to integrate with the synaptic (light) responses. Finally, although glia are often the earliest responder to mechanical stress, the mechanisms that impel mechanosensitivity to these cells and how they impact RGC physiology remain largely unknown. The proposed work addresses these confounds by identifying the mechanotransducers and elucidating their role in RGC and Müller glial calcium homeostasis and polymodal integration of pressure into the (patho)physiological retinal response. The project tests the central hypothesis that pressure sensitivity of dendrites, somata and axons of RGCs and glia is governed by mechanosensitive ion channels, which maintain tensile homeostasis and modulate calcium homeostasis, excitability and gliotransmitter release in response to changes in ocular pressure or strain. Leveraging the recently derived data and using novel mechanobiological tools, Aim 1 will identify and characterize mechanosensing ion channels in the RGC plasma membrane, quantify their activation by pressure and matrix stretch, and test the hypothesis that mechanical strains are transmitted from the plasma membrane into the cell interior through the cytoskeleton. In Aim 2 we propose to characterize the polymodal mechanism through which mechanical stimuli are integrated with the effects of temperature and synaptic (light) responses, and to test a novel hypothesis regarding the regulation of RGC tensile homeostasis. Aim 3 will characterize the molecular mechanisms whereby mechanically induced glial activation influences RGC physiology, thus providing insight into the early inflammatory mechanisms in diseases such as glaucoma. Taken together, the proposed studies may deepen our understanding of retinal function by uncovering new mechanisms that respond to acute and chronic mechanical forces and by reconciling currently disparate hypotheses about retinal pressure transduction. In addition, these studies will aid in the understanding of neurodegeneration that is required to optimize early diagnosis and neuroprotective treatment, which are currently lacking in glaucoma. During the last few years, mutations in putative mechanosensing ion channels have been shown to cause many human diseases and disorders, including severe dysplasias, gliovascular abnormalities and axonal neuropathies but their impact on visual signaling is unknown due to the absence of basic studies. The information provided by these studies may thus contribute insights into mechanosensitive mechanisms that underlie retinal disease as well as transduction of mechanical stress within the CNS.

视网膜神经节细胞和米勒神经胶质细胞特别容易受到机械力的影响，从而引发炎症 青光眼等疾病中的激活和 RGC 变性，但压力传导机制是 不太理解。早期的研究仅限于对遗传、分子、细胞和 高压引起的 RGC 损伤和神经胶质激活的行为后果。虽然很多 研究表明，高血压眼中的生化途径发生了改变，即转导信号的分子传感器 机械力仍然模糊不清，混淆了对压力引起的时间依赖性的解释 视网膜内的重塑变化。关于青光眼压力性损伤的主要假设集中在 力对筛板伸展的作用使小鼠患上这种疾病，但没有胶原蛋白 叶片。轴心假说也无法解释轻微的压力升高如何引起早期的变化 树突结构和突触功能，或激活神经胶质细胞，而轴突运输没有明显变化。这也是 尚不清楚眼压的生理水平如何影响 RGC 的生理学以及它们是否与 足以与突触（光）反应整合。最后，虽然神经胶质细胞通常是最早的反应者 对机械应力、促使这些细胞产生机械敏感性的机制以及它们如何影响 RGC 生理学在很大程度上仍然未知。 拟议的工作通过识别机械传感器并阐明其作用来解决这些混淆 RGC 和 Müller 胶质细胞钙稳态以及压力与（病理）生理的多模式整合 视网膜反应。该项目测试了树突、胞体和轴突的压力敏感性的中心假设 RGC 和神经胶质细胞的结构由机械敏感离子通道控制，维持张力稳态 调节钙稳态、兴奋性和神经胶质递质释放以响应眼压变化 或应变。利用最近获得的数据并使用新颖的机械生物学工具，目标 1 将识别和 表征 RGC 质膜中的机械传感离子通道，通过压力量化其激活 和基质拉伸，并检验机械应变从质膜传递的假设 通过细胞骨架进入细胞内部。在目标 2 中，我们建议描述多模态机制 通过它将机械刺激与温度和突触（光）反应的影响相结合， 并检验关于 RGC 张力稳态调节的新假设。目标 3 将描述 机械诱导神经胶质细胞活化影响 RGC 生理学的分子机制，从而提供 深入了解青光眼等疾病的早期炎症机制。综合起来，建议 研究可能会通过揭示响应急性反应的新机制来加深我们对视网膜功能的理解 和慢性机械力，并通过协调目前关于视网膜压力的不同假设 转导。 此外，这些研究将有助于理解早期优化所需的神经退行性变。 目前青光眼缺乏诊断和神经保护治疗。在过去的几年里， 假定的机械传感离子通道的突变已被证明会导致许多人类疾病和 疾病，包括严重发育不良、胶质血管异常和轴突神经病，但它们对 由于缺乏基础研究，视觉信号传导尚不清楚。这些研究提供的信息可能 从而有助于深入了解视网膜疾病和转导的机械敏感机制 中枢神经系统内的机械应力。