Autophagy and Mechanotransduction in the Trabecular Meshwork

小梁网中的自噬和力转导

• 批准号: 9979962
• 负责人: Paloma Liton
• 金额: $ 43.85万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2022-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9979962
• 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; Homeostasis; Injury; Laboratories; Lead; Mechanical Stress; Mechanics; Mediating; Metabolic; Modeling; Morphology; Mus; Ocular Hypertension; Organelles; Pathologic; Pathway interactions; Periodicity; Pharmacology; 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; Tissue Preservation; Tissues; Trabecular meshwork structure; Transforming Growth Factor beta; age related; base; clinically significant; connective tissue growth factor; cytokine; cytotoxic; drug development; experimental study; genetic activator; healing; inhibition of autophagy; mechanical force; mechanotransduction; new therapeutic target; novel; novel therapeutic intervention; novel therapeutics; preservation; pressure; prevent; repaired; response; wasting

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 小梁网（TM）传统流出道的功能失效导致 眼内压（IOP），从而增加患原发性开角型青光眼（POAG）的风险， 与年龄有关的疾病是导致不可逆失明的第二大原因。体内平衡机制 对于IOP调节以及与青光眼中IOP改变相关的因素仍然知之甚少。 由于IOP和其他力的升高，小梁网（TM）中的细胞不断受到 机械应变。为了保持细胞功能和恢复稳态，细胞必须感知和适应 这些形态学上的变化。我们和其他人已经证明，机械应力可以引发一种 TM细胞中广泛的反应;然而，关于TM细胞用于 对这种压力做出反应，这样它们才能适应并生存下来。 自噬是一种重要的细胞内环境稳定机制， 促进细胞存活和对许多细胞毒性应激的适应。我们的实验室报告说， TM细胞中响应于静态双轴应变和高压的自噬活化。此外，我们最新的 数据还表明伴侣辅助的选择性自噬的激活，这是一种最近发现的张力， 诱导自噬必不可少的机械转导，在TM细胞在循环机械应力。 我们假设自噬是TM细胞对应变的反应中触发的综合反应的一部分， 在修复和机械传导中发挥双重作用。我们进一步假设， 反应有助于增加ECM沉积和刚度报告在脑水肿流出 通路因此，我们认为自噬的激活可以代表一种新的治疗方法， 治疗高眼压和青光眼。为了验证这一假设，我们将（1）描述 在TM细胞中响应于机械应力和高压诱导自噬，并确定其 （2）评估自噬在调节TM细胞中的张力诱导反应中的作用; TGFβ介导的促纤维化对机械损伤的反应，和（3）评估药理学的能力， 自噬活化剂，以减少ECM沉积和恢复流出途径功能。我们预计 该项目的完成将有助于进一步了解自噬在 流出途径组织生理学和病理生理学。最重要的是，我们的研究有潜力 鉴定用于治疗高眼压和青光眼的新的治疗靶点。