Molecular mechanisms of mechanotransduction in the aqueous outflow pathway

项目总结/摘要 有大量证据表明高血压性青光眼显著改变了小梁的功能， 网状（TM）细胞，以科普机械应力，这反过来又有助于损害排水的水 前眼的幽默功能丧失与TM细胞及其基质的硬化有关， 内稳态机械感测的丧失，该内稳态机械感测将流出通路的阻力调节到 经历了压力和水状体流动的动力学。纤维化重塑，其基础是增加 流动阻力可由眼内压（IOP）的慢性升高或由细胞因子TGF β 1引起， 在没有机械应力的情况下诱发它。目前还没有概念性工具将IOP压力、阶段 TM损伤，TGF β 1调节和机械转导在健康和青光眼的眼睛成一个统一的 一致性机制模型 这种竞争性更新的目标是测试关于TM细胞如何操纵它们对压力的反应的假设， 剪切和应变，这些机制在青光眼中是如何重组的，基质硬度和TGF β是如何起作用的 通过机械敏感性通道，作为纤维化重塑的触发器， 青光眼目的1建立TRPV 4和Piezo 1通道在条件敲除条件下的眼压调节作用 小鼠模型和常规流出的离体研究。目的2研究了 异常的机械转导，研究细胞外基质作为中枢神经系统的作用。 机械敏感性的决定因素，剖析TRPV 4基因/蛋白质之间的矛盾不协调 表达和功能，并测试有关机械通道参与细胞内应激的假设 信号传导、收缩性、上皮间质转化和细胞增殖潜能的调节。目标 目的3是将机械转导和TGF β 1信号转导整合到一个统一的框架中， 解释了许多类型青光眼的生物物理（机械）和生物化学诱导。完成后 通过这项研究，我们希望扩大我们对连锁分子机制复杂性的理解， 通过它TM调节流出设施，定义青光眼劫持的分子触发器 通过机械敏感离子通道、整合素和细胞骨架的稳态力传感，并鉴定 通过恢复细胞自动调节机械反应的能力来减轻损伤的策略。

PROJECT SUMMARY/ABSTRACT There is substantial evidence that hypertensive glaucoma dramatically alters the capacity of trabecular meshwork (TM) cells to cope with mechanical stress, which in turn contributes to impaired drainage of aqueous humor from the anterior eye. Functional loss is associated with stiffening of TM cells and their matrix, and with loss of homeostatic mechanosensing that adjusts the resistance of the outflow pathway to the intensity of experienced pressure and dynamics of aqueous humor flow. Fibrotic remodeling that underlies the increase in flow resistance can be caused by chronic elevations in intraocular pressure (IOP) or by the cytokine TGF which induces it in the absence of mechanical stress. There are currently no conceptual tools to link IOP stress, stages of TM damage, TGF modulation and mechanotransduction in healthy and glaucomatous eyes into a unified coherent mechanistic model. The goal of this competing renewal is to test hypotheses about how TM cells navigate their response to pressure, shear, and strain, how these mechanisms are reorganized in glaucoma and how matrix stiffness and TGF act through mechanosensitive channels to serve as triggers for fibrotic remodeling that leads to functional loss in glaucoma. Aim 1 will establish the roles of TRPV4 and Piezo1 channels in IOP regulation in conditional knockout mouse models and ex vivo studies of conventional outflow. Aim 2 investigates the molecular foundation of abnormal mechanotransduction in glaucomatous TM cells, studies the role of extracellular matrix as a central determinant of mechanosensitivity, dissects the paradoxical dissonance between TRPV4 gene/protein expression and function, and tests hypotheses about involvement of mechanochannels in intracellular stress signaling, contractility, epithelial mesenchymal transition and regulation of cells’ proliferative potential. The goal of Aim 3 is to bring together mechanotransduction and TGF signaling into a unified framework that would accounts for biophysical (mechanical) and biochemical induction of many types of glaucoma. Upon completion of the study we hope to expand our understanding of the complexity of interlocked molecular mechanisms through which the TM regulates outflow facility, define the molecular triggers through which glaucoma hijacks homeostatic force sensing by mechanosensitive ion channels, integrins and the cytoskeleton, and identify strategies to mitigate injury by restoring the cells ability to autoregulate the mechanoresponse.