Molecular mechanisms of mechanotransduction in the aqueous outflow pathway

房水流出途径中力转导的分子机制

• 批准号: 10665244
• 负责人: DAVID KRIZAJ
• 金额: $ 38.5万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-01 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10665244
• 关键词: Ablation; Affect; Agonist; Anterior; Aqueous Humor; Autophagocytosis; Biochemical; Biology; Biomechanics; Biophysics; Blindness; Calcium; Cell Communication; Cells; Cellular Stress; Chronic; Cues; Cytoskeleton; Dependence; Drainage procedure; Environment; Epithelium; Extracellular Matrix; Eye; Eye diseases; Fibrosis; Foundations; Gene Expression; Genes; Glaucoma; Goals; Homeostasis; Impairment; Individual; Injury; Integrins; Ion Channel; Knockout Mice; Lead; Link; Literature; Mechanical Stress; Mechanics; Mediating; Mediator; Membrane; Membrane Microdomains; Mesenchymal; Metabolism; Modality; Modeling; Molecular; Mus; Myofibroblast; Ocular Hypertension; Open-Angle Glaucoma; Pathologic; Pathway interactions; Permeability; Pharmacotherapy; Physiologic Intraocular Pressure; Physiological; Piezo 1 ion channel; Predisposition; Regulation; Resistance; Risk Factors; Role; Signal Transduction; Specific qualifier value; Stimulus; Stress; Structure of sinus venosus of sclera; Swelling; Testing; Tissues; Trabecular meshwork structure; Transducers; Work; aged; antagonist; aqueous; aqueous humor flow; conditional knockout; coping; cytokine; experience; functional loss; hypertensive; interest; knowledge base; mechanical properties; mechanotransduction; mouse model; normotensive; novel; pharmacologic; potassium channel protein TREK-1; pressure; profibrotic cytokine; protein expression; protein function; response; rho; success; tool; transdifferentiation

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.

项目摘要/摘要 有充分的证据表明，高血压青光眼极大地改变了小梁的能力 网状功能（TM）细胞应对机械应力，这又有助于水的排水不足 前眼的幽默。功能丧失与TM细胞及其基质的僵硬有关，以及 稳态机制的丧失，以调整出口途径的电阻到强度 幽默流动的压力和动力学。纤维化重塑是基础的增加 流量阻力可能是由眼内压（IOP）的慢性升高或细胞因子TGF引起的 在没有机械应力的情况下诱导它。当前没有概念工具可以连接压力，阶段 健康和青光眼的眼睛中的TM损伤，TGF调制和机械转传入​​统一的 连贯的机理模型。 这种竞争更新的目的是测试有关TM细胞如何导航压力的假设， 剪切和应变，这些机制如何在青光眼中重组以及基质刚度和TGF如何作用 通过机械敏感的通道，充当触发器进行纤维化重塑的触发器，导致功能损失 青光眼。 AIM 1将在条件敲除中建立TRPV4和Piezo1通道的作用 小鼠模型和传统流出的离体研究。 AIM 2研究了分子基础 青光眼TM细胞中的机械转导异常，研究细胞外基质作为中央的作用 机理敏感性的决定因素，剖析了TRPV4基因/蛋白质之间的矛盾失调 表达和功能，并检验有关机械通道参与细胞内应力的假设 信号传导，收缩力，上皮间充质转变和细胞增殖潜力的调节。目标 AIM 3中的是将机械转移和TGF信号汇集到一个统一的框架中 对许多类型的青光眼的生物物理（机械）和生化诱导的解释。完成后 在研究中，我们希望扩大我们对互锁分子机制复杂性的理解 TM通过其调节输出效率，定义分子触发因素，青光眼劫持了。 机械敏感的离子通道，整联蛋白和细胞骨架的稳态敏感性，并识别 通过恢复细胞自动调节机理响应的能力来减轻伤害的策略。