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Molecular mechanisms of mechanotransduction in the aqueous outflow pathway

房水流出途径中力转导的分子机制

基本信息

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
项目类别：
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

项目摘要

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.

项目总结/文摘