Autophagy and Mechanotransduction in the Trabecular Meshwork

小梁网中的自噬和力转导

• 批准号: 10570836
• 负责人: Paloma Liton
• 金额: $ 45.32万
• 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 2025-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10570836
• 关键词: Actins; Aging; Anterior; Anterior eyeball segment structure; Applications Grants; Aqueous Humor; Area; Autophagocytosis; Binding; Cell Nucleolus; Cells; Cilia; Circadian Rhythms; Collagen; Couples; Cytoskeleton; Data; Drainage procedure; Endothelium; Extracellular Matrix; Eye; Eye Movements; Family suidae; Functional disorder; Gene Expression; Glaucoma; Goals; Homeostasis; Human; Injury; Laboratories; Length; Loose connective tissue; MADH2 gene; Mechanical Stress; Mechanics; Nature; Nuclear; Nuclear Translocation; Ocular Hypertension; Pathologic; Pathway interactions; Perfusion; Physiologic Intraocular Pressure; Physiologic pulse; Physiological; Physiology; Play; Prevalence; Proteomics; Proto-Oncogene Proteins c-akt; Regulation; Relaxation; Reporting; Risk Factors; Role; Signal Pathway; Signal Transduction; Stress; Stretching; Testing; Time; Tissues; Trabecular meshwork structure; Transforming Growth Factor beta; Transgenic Mice; Translating; Variant; cilium biogenesis; coping; cytokine; experimental study; fluid flow; healing; innovation; mechanical force; mechanotransduction; mouse model; new therapeutic target; novel; novel therapeutic intervention; pharmacologic; pressure; prevent; proteostasis; repaired; response

ABSTRACT The trabecular meshwork (TM) is a pressure sensitive tissue located in the anterior segment of the eye, key regulator of intraocular pressure. Malfunction of this tissue results in improper drainage of aqueous humor (AH) outflow, leading to ocular hypertension, the major risk factor for developing glaucoma. The TM consists of an irregular lattice of collagen beams lined by TM endothelial-like cells, followed a zone of loose connective tissue- containing TM cells, through which AH must pass before leaving the eye. Changes in pressure gradients and fluid flow associated with eye movement, circadian rhythm or the ocular pulse cause small and high variations in intraocular pressure (IOP), which are translated in continuous cycles of tissue deformation and relaxation. Cells in the TM are known to be able of sensing these deformations as mechanical forces and respond to them by eliciting a variety of different responses. Our laboratory has identified activation of autophagy and the nuclear translocation of the autophagy marker LC3, in TM cells following application of mechanical stretch. Activation of autophagy was also observed in TM cells quickly after pressure elevation in porcine perfused eyes and in ocular hypertensive mouse models. This prompted us to propose autophagy as a crucial physiological response triggered in TM cells in response to strain to adapt to mechanical forces and maintain cellular homeostasis, which exerts a dual role in repair and mechanotransduction. The nature of the mechanosensor, mechanosignaling, and exact roles of autophagy in TM cell and tissue function are still not characterized. The goal of this application is to investigate an interplay between autophagy, primary cilium and mechanotransduction in TM cells and to determine the role of such interplay in outflow pathway physiology and pathophysiology. More in particular, we will test the hypothesis that autophagy plays a critical role in TM mechanotransduction by maintaining primary cilia prevalence and length, and that dysregulation of autophagy with aging and in the glaucomatous outflow pathway compromises primary cilia-dependent IOP homeostatic response. We anticipate that completion of this project will contribute to a further understanding of the role of autophagy in outflow pathway tissue physiology and pathophysiology. Most relevant, 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）是位于眼前段的压力敏感组织， 眼内压调节器。该组织的功能障碍导致房水（AH）引流不当 外流，导致高眼压，发展青光眼的主要危险因素。技术备忘录包括 不规则的胶原束网格排列着TM内皮样细胞，紧接着是疏松结缔组织区， 含有TM细胞，AH在离开眼睛之前必须通过TM细胞。压力梯度的变化， 与眼睛运动、昼夜节律或眼脉冲相关的流体流动引起小而高的变化 在眼内压（IOP），这是在组织变形和松弛的连续循环中转换。 已知TM中的细胞能够将这些变形感知为机械力并对其做出响应 by elicitating引发a variety品种of different不同reactions反应. 我们的实验室已经确定了自噬的激活和自噬标志物LC 3的核转位， 在TM细胞中施加机械拉伸后。在TM细胞中也观察到自噬的激活 在猪灌注眼和高眼压小鼠模型中，这 促使我们提出自噬是TM细胞因应变而引发的一种重要生理反应 以适应机械力并维持细胞内稳态，这在修复和 机械传导机械传感器的性质，机械信号，以及自噬在细胞内的确切作用。 TM细胞和组织功能仍然没有表征。 本申请的目的是研究自噬，初级纤毛和 TM细胞中的机械转导，并确定这种相互作用在流出途径生理学和 病理生理学更具体地说，我们将测试自噬在TM中起关键作用的假设， 通过维持初级纤毛普遍性和长度的机械转导，以及自噬的失调 随着年龄的增长，在青光眼流出途径中， 反应我们预计，该项目的完成将有助于进一步了解 流出道组织生理学和病理生理学中的自噬。最重要的是，我们的研究 潜在的识别用于治疗高眼压症和青光眼的新的治疗靶点。