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：
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
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/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

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.

抽象的小梁网 (TM) 传统流出通路的功能故障导致眼内压（IOP），从而增加患原发性开角型青光眼（POAG）的风险与年龄相关的疾病是导致不可逆性失明的第二大原因。对于眼压调节以及与青光眼改变相关的调节仍知之甚少。由于眼压升高和其他力，小梁网 (TM) 中的细胞不断受到影响为了保持细胞功能并恢复稳态，细胞必须感知和适应。我们和其他人已经证明机械应力可以引发这些形态变化。 TM 细胞中的广泛反应；然而，人们对 TM 细胞使用的策略知之甚少。应对这种压力，以便他们能够适应和生存。自噬是一种溶酶体降解途径，已成为一种重要的细胞稳态机制促进细胞存活和适应多种细胞毒性应激。 TM 细胞响应静态双轴应变和高压而激活自噬此外，我们最新的。数据还表明伴侣辅助选择性自噬的激活，这是最近发现的一种张力- 在循环机械应力下的 TM 细胞中诱导自噬对于机械转导至关重要。我们探索自噬是 TM 细胞响应应变而触发的综合反应的一部分，我们进一步研究了这种失调。反应导致青光眼流出液中 ECM 沉积和硬度增加因此，我们认为自噬的激活可以代表一种新的治疗方法。高眼压症和青光眼的治疗为了检验这一假设，我们将 (1) 描述 TM 细胞响应机械应力和高压诱导自噬，并确定其 (2) 评估自噬在调节中的作用 TGFβ介导的对机械损伤的促纤维化反应，以及（3）评估药理作用的能力我们预计自噬激活剂可减少 ECM 沉积并恢复流出途径功能。该项目的完成无疑将有助于进一步了解自噬在最重要的是，我们的研究具有流出途径组织生理学和病理生理学的潜力。确定治疗高眼压症和青光眼的新治疗靶点。