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müller神经胶质特别容易受到驱动炎症的机械力 诸如青光眼等疾病中的激活和RGC变性，但压力转移机制是 不太了解。早期的研究仅限于表型遗传，分子，细胞和 升高压力引起的RGC损伤和神经胶质激活的行为后果。而很多 显示生化途径在高血压眼​​中发生了改变，这是转导的分子传感器 机械力保持晦涩难懂，对压力诱导的时间依赖性的混淆解释 视网膜内的重塑变化。关于青光眼中的压力损伤的主要假设集中在 力在椎板骨的延伸中的作用，但小鼠发展了这种疾病，但没有胶原蛋白 薄片。轴心的假设也无法解释轻度压力高度如何 树突状结构和突触功能，或激活胶质神经胶质，而没有明显变化的轴突运输。也是 尚不知道眼内压力的物理水平可能会为RGC生理提供信息以及它们是否是 足以与突触（光）响应集成。最后，尽管神经胶质通常是最早的响应者 在机械应力下，将机制敏感的机制促进了这些细胞以及它们如何影响RGC 生理学仍然在很大程度上未知。 拟议的工作通过识别机械转换器并阐明其作用来解决这些混杂 在RGC和Müller神经胶质钙稳态中，压力将压力整合到（病原）生理中 视网膜反应。该项目检验了一个中心假设，即树突，躯体和轴突的压力敏感性 RGC和Glia的机械敏感离子通道管辖，这些通道保持拉伸稳态和 调节钙稳态，兴奋性和闪光灯闪光灯释放，以应对眼压的变化 或应变。利用最近派生的数据并使用新颖的机械工具，AIM 1将识别和 表征RGC质膜中的机理性离子通道，通过压力量化其激活 和矩阵拉伸，并检验了从质膜传播机械菌株的假设 通过细胞骨架进入细胞内部。在AIM 2中，我们建议表征多峰机制 通过哪些机械刺激与温度和突触（光）响应的影响整合在一起， 并检验一个有关RGC拉伸稳态调节的新假设。 AIM 3将表征 机械诱导神经胶质激活影响RGC生理的分子机制，从而提供了 洞悉诸如青光眼等疾病的早期炎症机制。两者一起，提议 研究可以通过发现对急性反应的新机制来加深我们对视网膜功能的理解 和慢性机械力以及通过对当前关于永久压力的不同假设进行核对 转导。 此外，这些研究将有助于理解早期优化的神经变性 目前缺乏青光眼的诊断和神经保护治疗。在过去的几年中， 渠道中假定机制中的突变已显示导致许多人类疾病，并且 疾病，包括严重的发育不良，神经血管异常和轴突神经病，但它们对 由于没有基础研究，视觉信号传导未知。这些研究提供的信息可能 因此，有助于洞悉残留疾病和翻译基础的机理敏感机制 中枢神经系统内的机械应力。