Molecular mechanisms of mechanotransduction in the aqueous outflow pathway

房水流出途径中力转导的分子机制

• 批准号: 10133080
• 负责人: DAVID KRIZAJ
• 金额: $ 36.98万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-01 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10133080
• 关键词: Actins; Acute; Anterior; Aqueous Humor; Biological Assay; Biology; Biomedical Engineering; Biomimetics; Biophysics; Blindness; Calcium; Cattle; Cells; Chronic; Contracts; Coupling; Cytoskeleton; Development; Drainage procedure; Electrophysiology (science); Etiology; Extracellular Matrix; Eye; Fluorescence Resonance Energy Transfer; Focal Adhesions; Gene Expression; Geometry; Glaucoma; Homeostasis; Human; Hydrostatic Pressure; Lead; Link; Liquid substance; Mechanical Stress; Mechanics; Mediating; Modeling; Molecular; Molecular Biology; Mus; Optics; Pathologic; Pathway interactions; Patients; Periodicity; Pharmacotherapy; Phospholipase A2; Physiologic Intraocular Pressure; Play; Potassium; Property; Protein Isoforms; Proteins; Regulation; Research; Resistance; Retina; Risk Factors; Rodent; Role; Signal Pathway; Stress; Stress Fibers; Stretching; Swelling; Testing; Time; Tissues; Trabecular meshwork structure; Translating; Up-Regulation; aqueous; base; biological adaptation to stress; effective therapy; innovation; mechanical force; mechanotransduction; novel; optical imaging; pre-clinical; pressure; prevent; real-time images; receptor; response; rho; success; therapeutically effective

PROJECT SUMMARY/ABSTRACT There is substantial evidence that pathological increases in intraocular pressure (IOP) play a causal role in the pathological remodeling of trabecular meshwork cells which regulate the drainage of aqueous humor from the anterior eye however the identity and function of the mechanosensing mechanisms remains largely unknown. The present proposal aims to characterize these mechanisms at biophysical, molecular and cellular levels as well as in bioengineered models of conventional outflow. Aim 1 will establish the mechanical thresholds of human TM cells obtained from non-symptomatic and glaucomatous patients, characterize effect of mechanical stress (pressure, stretch and swelling) on intrinsic mechanosensitive channels and establish its time- dependent properties (acute & chronic adaptation). This is expected to lead to a novel model of tensile homeostasis in the TM based on balanced activation of opposing types of mechanosensitive channels. Aim 2 links pressure-sensitive channels to the remodeling of actin cytoskeleton and focal adhesion contacts with the extracellular matrix, uses innovative strain-sensitive optical cytoskeleton probes and defines the function of mechanical coupling in the regulation of the conventional outflow resistance using biomimetic nanoscaffolds populated with healthy and glaucomatous human TM cells. The proposed research thus aims to establish novel conceptual, experimental and translational frameworks that will unify our understanding of retinal IOP regulation within the context of mechanotransduction, cell swelling, volume sensing and calcium homeostasis, with the aim to lead towards the development of effective, first-in-kind treatments for glaucoma.

项目概要/摘要 有大量证据表明眼内压（IOP）的病理性升高在 小梁网细胞的病理重塑，调节房水从房水的排出 然而，前眼机械传感机制的身份和功能仍然很大程度上未知。 本提案旨在在生物物理、分子和细胞水平上表征这些机制： 以及传统流出的生物工程模型。目标 1 将建立机械阈值 从无症状和青光眼患者身上获得的人类 TM 细胞，表征机械效应的影响 内在机械敏感通道上的应力（压力、拉伸和膨胀）并确定其时间 依赖性特性（急性和慢性适应）。预计这将产生一种新的拉伸模型 TM 中的稳态基于相反类型的机械敏感通道的平衡激活。目标2 将压力敏感通道与肌动蛋白细胞骨架的重塑和焦点粘附接触联系起来 细胞外基质，使用创新的应变敏感光学细胞骨架探针并定义了 使用仿生纳米支架调节传统流出阻力的机械耦合 充满健康和青光眼人类 TM 细胞。因此，拟议的研究旨在建立 新颖的概念、实验和转化框架将统一我们对视网膜眼压的理解 在机械转导、细胞肿胀、体积传感和钙稳态的背景下进行调节， 旨在引领开发有效的、同类首创的青光眼治疗方法。