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; 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.

抽象的 小梁网（TM）是位于眼前部分的压力敏感组织，钥匙 眼内压的调节剂。该组织的故障导致水幽默的排水不正确（AH） 流出，导致眼高血压，这是发展青光眼的主要危险因素。 TM由 由TM内皮样细胞衬里的胶原蛋白束的不规则晶格，跟随一个松散的结缔组织区域 包含TM细胞，在离开眼睛之前必须通过AH经过。压力梯度的变化和 与眼动，昼夜节律或眼部脉冲有关的流体流量会引起较小和高的变化 在眼内（IOP）中，它们以组织变形和松弛的连续循环进行翻译。 已知TM中的细胞能够将这些变形作为机械力传感并响应 通过引起各种不同的反应。 我们的实验室已经确定了自噬的激活和自噬标记LC3的核易位， 在应用机械拉伸后，在TM细胞中。在TM细胞中也观察到自噬的激活 在猪灌注眼和眼部高血压小鼠模型中压力升高后，很快。这 促使我们提出自噬作为在TM细胞中触发的关键生理反应，以应对菌株 适应机械力并维持细胞稳态，这在修复和 机械转导。机械传感器的性质，机械信号和自噬在 TM细胞和组织功能仍未表征。 该应用的目的是研究自噬，原发性纤毛和 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和 病理生理学。特别是，我们将测试自噬在TM中起关键作用的假设 通过维持原发性纤毛的患病率和长度和自噬的失调来传导机械转传 随着衰老和青光眼流出途径，损害了依赖纤毛的IOP稳态 回复。我们预计该项目的完成将有助于进一步了解 自噬在流出途径组织生理和病理生理学中。最相关的是，我们的研究有 鉴定新的治疗靶标的眼睛高血压和青光眼治疗的潜力。