Autophagy and Mechanotransduction in the Trabecular Meshwork

小梁网中的自噬和力转导

• 批准号: 9756413
• 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 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9756413
• 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.

抽象的 小梁网格林（TM）常规出口通路的功能故障导致高度 眼内压（IOP），从而增加了发展初级开头青光眼（POAG）的风险 与年龄相关的疾病的不可逆转失明的第二主要原因。负责稳态机制 对于IOP调节和与青光眼改变的调节有关的调节仍然尚未理解。 由于IOP和其他力的升高，小梁网中的细胞（TM）不断受到 到机械应变。为了保留细胞功能并保持体内稳态，细胞必须感知和适应 这些形态学变化。我们和其他人已经表明，机械压力会触发 TM细胞中的广泛反应；但是，关于TM单元使用的策略知之甚少 应对这种压力，因此他们可以适应并生存。 自噬是一种溶酶体降解途径，已成为重要的细胞稳态机制 促进细胞存活并适应许多细胞毒性应激。我们的实验室报告了 响应静态双轴菌株和高压的TM细胞中自噬的激活。而且，我们的最新 数据还表明激活伴侣辅助选择性自噬，最近确定的张力 - 在循环机械应力下TM细胞中的机械转移至关重要的自噬所诱导的自噬。 我们假设自噬是TM细胞中触发的综合响应的一部分，该反应响应于应变， 在修复和机械转导中发挥双重作用。我们进一步假设这是对此的失调 响应有助于增加青光眼出口中报告的ECM沉积和刚度 路径。我们建议自噬的激活可以代表一种新颖的治疗方法 治疗眼高血压和青光眼。为了检验这一假设，我们将（1）表征 响应机械应力和高压诱导TM细胞中自噬的诱导，并确定其 对TM细胞中拉伸诱导反应的贡献； （2）评估自噬在调节 TGFβ介导的对机械损伤的促纤维化反应，（3）评估药理学的能力 自噬的激活剂可减少ECM沉积并恢复出口途径功能。我们预料到这一点 该项目的完成将有助于进一步理解自噬在 出口途径组织生理和病理生理学。最重要的是，我们的研究具有 鉴定出一种新型的热靶标，用于治疗眼高血压和青光眼。