Optic Nerve Head Mechanobiology in Glaucoma

青光眼视神经乳头力学生物学

• 批准号: 9895804
• 负责人: J CRAWFORD DOWNS
• 金额: $ 44.78万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9895804
• 关键词: 3-Dimensional; Actins; Acute; Adult; Anatomy; Animal Model; Autopsy; Axon; Biomechanics; Blindness; Cells; Cellular Mechanotransduction; Cessation of life; Characteristics; Chronic; Clinical; Computer Models; Connective Tissue; Cytoskeleton; Data; Development; Disease; Disease Progression; Environment; Extracellular Matrix; Eye; Fibroblasts; Frequencies; Functional disorder; Future; Glaucoma; Goals; Harvest; Human; Image; Immunohistochemistry; In Vitro; Individual; Knowledge; Lead; Measures; Mechanics; Modeling; Molecular; Morphology; Myofibroblast; Optic Disk; Optical Coherence Tomography; Pathogenesis; Pathologic; Pathway interactions; Patients; Physiologic Intraocular Pressure; Play; Predisposition; Property; Proxy; Records; Regulation; Retinal Ganglion Cells; Risk Factors; Role; Sclera; Severities; Signal Transduction; Stress; Structure; Telemetry; Testing; Thrombospondin 1; Tissues; Transforming Growth Factor beta; Weight-Bearing state; Wireless Technology; axon injury; base; effective therapy; human tissue; in silico; in vivo; mechanotransduction; modifiable risk; new therapeutic target; nonhuman primate; novel; prevent; reconstruction; response; therapeutic development

ABSTRACT Glaucoma is the second leading cause of blindness in the developed world. Alterations in optic nerve head (ONH) biomechanics and pathologic remodeling of associated connective tissues in the lamina cribrosa (LC) and scleral are thought to be important in glaucomatous retinal ganglion cell axonal damage and vision loss. Elevated intraocular pressure (IOP) is the only modifiable risk factor for glaucoma, although vision loss can occur at normal IOP. IOP is a stress that imparts strain to the ONH. The role that mechanical strain and the underlying cellular mechanotransduction pathways play in pathologic connective tissue remodeling of the ONH and sclera in glaucoma remain poorly understood, however. Our central hypothesis is that cellular-level strain, modulated by laminar and scleral tissue stiffness, drives mechanotransduction responses that cause pathologic alterations in the ONH and scleral connective tissue/extracellular matrix (ECM) and lead to axonal death. Furthermore, we propose that these factors underlie the variability in glaucoma susceptibility and progression at all IOP levels. The goals of this proposal are to 1) to identify the biomechanical factors that contribute to glaucoma susceptibility, and 2) identify the biomechanical and molecular determinants of mechanically-induced cellular responses and connective tissue remodeling in glaucoma. To achieve this goal, we will use a unilateral, inducible animal model of glaucoma with identical IOP endpoints, and human donor eyes. In Aim 1, we will identify biomechanical risk factors for glaucoma and determine remodeling-induced alterations in morphology and mechanical responses of the LC and sclera using optical coherence tomography and 3D reconstructions. We will also determine the effect of chronic elevated IOP on mechanotransduction/ECM remodeling pathways in tissues and cells harvested from this model at a defined IOP insult and correlate this activity with changes in scleral/ONH material properties and axon loss. In Aim 2, we will determine whether the pathways identified in the animal model are similarly regulated clinical records- verified normal and glaucomatous human donor eyes. In Aim 3, we will determine the mechanical environment that stimulates tissue remodeling using eye specific, multi-scale 3D computational models of eyes. These studies will lead to identification of both biomechanical factors and cellular mechanotransduction pathways that contribute to scleral/ONH ECM remodeling and glaucoma pathogenesis, with the goal of identifying new therapeutic targets.

摘要 青光眼是发达国家的第二大致盲原因。视神经乳头改变 (ONH)筛板（LC）中相关结缔组织的生物力学和病理重塑 和巩膜被认为在青光眼视网膜神经节细胞轴突损伤和视力丧失中是重要的。 眼内压升高（IOP）是青光眼唯一可改变的危险因素，尽管视力丧失可能 发生在正常IOP下。IOP是对ONH施加应变的应力。机械应变和 潜在的细胞机械传导通路在ONH的病理性结缔组织重塑中起作用 然而，青光眼中的巩膜仍然知之甚少。我们的核心假设是细胞水平的应变， 由板层和巩膜组织硬度调制，驱动机械转导反应， ONH和巩膜结缔组织/细胞外基质（ECM）的病理改变，并导致轴突 死亡此外，我们认为这些因素是青光眼易感性变异的基础， 所有IOP水平的进展。该建议的目标是：1）确定生物力学因素， 有助于青光眼易感性，和2）确定生物力学和分子决定因素， 青光眼中机械诱导的细胞反应和结缔组织重塑。为了实现这一目标， 我们将使用具有相同IOP终点的单侧可诱导青光眼动物模型， 眼睛在目标1中，我们将确定青光眼的生物力学危险因素，并确定重塑诱导的 使用光学相干断层扫描术改变LC和巩膜的形态和机械响应 和3D重建。我们还将确定慢性高眼压对 机械转导/ECM重塑途径在从该模型中收获的组织和细胞中在定义的浓度下， IOP损伤并将该活性与巩膜/ONH材料性质的变化和轴突损失相关联。在目标2中， 我们将确定在动物模型中确定的途径是否是类似的受监管的临床记录- 确认了正常和昏迷的人类供体眼睛。在目标3中，我们将确定机械环境 其使用眼睛的眼睛特异性、多尺度3D计算模型来刺激组织重塑。这些 研究将导致生物力学因素和细胞力学转导途径的鉴定， 有助于巩膜/ONH ECM重塑和青光眼发病机制，目的是鉴定新的 治疗目标