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.

抽象的 青光眼是发达国家第二大失明原因。视神经乳头的改变 (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很重要。 眼内压升高（IOP）是青光眼唯一可改变的危险因素，尽管视力丧失可导致青光眼。 发生在正常眼压时。 IOP 是一种会给 ONH 带来压力的压力。机械应变的作用和 潜在的细胞力转导途径在 ONH 的病理结缔组织重塑中发挥作用 然而，青光眼中的巩膜和巩膜仍然知之甚少。我们的中心假设是细胞水平的应变， 由层状和巩膜组织硬度调节，驱动机械传导反应，导致 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和青光眼易感性变异的基础。 所有 IOP 水平的进展。该提案的目标是 1) 确定生物力学因素 有助于青光眼易感性，2）确定青光眼的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 终点的单侧诱导青光眼动物模型和人类捐赠者 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引起的 使用光学相干断层扫描改变 LC 和巩膜的形态和机械反应 和 3D 重建。我们还将确定慢性眼压升高对 从该模型中以定义的速度收获的组织和细胞中的机械转导/ECM 重塑途径 IOP 损伤并将这种活动与巩膜/ONH 材料特性和轴突损失的变化相关联。在目标 2 中， 我们将确定动物模型中确定的途径是否受到类似监管的临床记录- 验证了正常和青光眼的人类供体眼睛。在目标 3 中，我们将确定机械环境 使用眼睛特定的多尺度 3D 计算模型刺激组织重塑。这些 研究将导致生物力学因素和细胞机械传导途径的识别 有助于巩膜/ONH ECM 重塑和青光眼发病机制，目标是识别新的 治疗目标。