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Autophagy and Mechanotransduction in the Trabecular Meshwork

小梁网中的自噬和力转导

基本信息

批准号：
9147858
负责人：
Paloma Liton
金额：
$ 43.85万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-01 至 2021-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9147858
关键词：
Aging Anterior Applications Grants Autophagocytosis Autophagosome Blindness Cell Survival Cell physiology Cells Collagen Data Degradation Pathway Deposition Disease Extracellular Matrix Extracellular Matrix Degradation Eye Movements Failure Fibrosis Functional disorder Glaucoma Healed Homeostasis Injury Laboratories Lead Life Mechanical Stress Mechanics Mediating Metabolic Modeling Molecular Chaperones Mus Ocular Hypertension Organelles Pathway interactions Physiologic Intraocular Pressure Physiological Physiology Play Primary Open Angle Glaucoma Process Production Proteins Publishing Regulation Reporting Research Risk Role Smooth Muscle Actin Staining Method Starvation Stress Stretching Testing Tissues Trabecular meshwork structure Transforming Growth Factor beta age related base clinically significant connective tissue growth factor coping cytokine cytotoxic drug development genetic activator healing inhibition of autophagy new therapeutic target novel novel therapeutic intervention novel therapeutics pressure prevent repaired research study response wasting

项目摘要

ABSTRACT Functional failure of the trabecular meshwork (TM) conventional outflow pathway causes elevation in intraocular pressure (IOP), thus increasing the risk for developing primary open angle glaucoma (POAG) an age-related disease second leading cause of irreversible blindness. The homeostatic mechanisms responsible for IOP regulation and those associated with its alteration in glaucoma remain yet poorly understood. Because of elevation in IOP and other forces, cells in the trabecular meshwork (TM) are constantly subjected to mechanical strain. In order to preserve cellular function and regain homeostasis, cells must sense and adapt to these morphological changes. We and others have already shown that mechanical stress can trigger a broad range of responses in TM cells; however, very little is known about the strategies that TM cells use to respond to this stress, so they can adapt and survive. Autophagy, a lysosomal degradation pathway, has emerged as an important cellular homeostatic mechanism promoting cell survival and adaptation to a number of cytotoxic stresses. Our laboratory has reported the activation of autophagy in TM cells in response to static biaxial strain and high pressure. Moreover, our newest data also suggest the activation of chaperon-assisted selective autophagy, a recently identified tension- induced autophagy essential for mechanotransduction, in TM cells under cyclic mechanical stress. We hypothesize that autophagy is part of an integrated response triggered in TM cells in response to strain, exerting a dual role in repair and mechanotransduction. We further hypothesize that dysregulation of this response contributes to the increased ECM deposition and stiffness reported in the glaucomatous outflow pathway. We propose that activation of autophagy can, therefore, represent a novel therapeutic approach for the treatment of ocular hypertension and glaucoma. To test this hypothesis, we will (1) characterize the induction of autophagy in TM cells in response to mechanical stress and high pressure and determine its contribution to the stretch-induced response in TM cells; (2) assess a role of autophagy in modulating the TGFβ-mediated pro-fibrotic response to mechanical injury, and (3) evaluate the ability of pharmacological activators of autophagy to decrease ECM deposition and restore outflow pathway function. We anticipate that completion of this project will definitively contribute to a further understanding of the role of autophagy in outflow pathway tissue physiology and pathophysiology. Most importantly, our studies have the potential of identifying a novel therapeutic target for the treatment of ocular hypertension and glaucoma.

摘要