Autophagy and Mechanotransduction in the Trabecular Meshwork

小梁网中的自噬和力转导

• 批准号: 10390022
• 负责人: Paloma Liton
• 金额: $ 44.84万
• 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/10390022
• 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; Pharmacology; 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; Transgenic Mice; Translating; Variant; cilium biogenesis; cytokine; experimental study; fluid flow; healing; innovation; mechanical force; mechanotransduction; mouse model; new therapeutic target; novel; novel therapeutic intervention; 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.

抽象的 小梁网 (TM) 是位于眼前节的压力敏感组织，是眼睛的关键 眼压调节剂。该组织的功能障碍导致房水 (AH) 引流不当 流出，导致高眼压，这是发生青光眼的主要危险因素。 TM 由一个 胶原蛋白束的不规则晶格，排列着TM内皮样细胞，后面是疏松结缔组织区域- 含有 TM 细胞，AH 在离开眼睛之前必须通过该细胞。压力梯度的变化和 与眼球运动、昼夜节律或眼脉搏相关的液体流动会导致小而高的变化 眼内压（IOP），其转化为组织变形和松弛的连续循环。 TM 中的细胞能够将这些变形感知为机械力并对其做出反应 通过引发各种不同的反应。 我们的实验室已经鉴定出自噬的激活和自噬标记物 LC3 的核转位， 应用机械拉伸后的 TM 细胞中。在 TM 细胞中也观察到自噬的激活 在猪灌注眼睛和高眼压小鼠模型中，压力升高后很快。这 促使我们提出自噬是 TM 细胞响应应变而触发的重要生理反应 适应机械力并维持细胞稳态，在修复和修复中发挥双重作用 力传导。机械传感器的性质、机械信号传导以及自噬的确切作用 TM 细胞和组织功能仍未得到表征。 该应用的目的是研究自噬、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，我们将检验自噬在 TM 中发挥关键作用的假设 通过维持初级纤毛的普遍性和长度进行机械转导，以及自噬失调 随着年龄的增长和青光眼流出途径会损害初级纤毛依赖的 IOP 稳态 回复。我们预计该项目的完成将有助于进一步了解 流出途径组织生理学和病理生理学中的自噬。最相关的是，我们的研究有 确定治疗高眼压症和青光眼的新治疗靶点的潜力。