Optic Nerve Head Mechanobiology in Glaucoma

青光眼视神经乳头力学生物学

基本信息

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
项目类别：
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

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

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项目摘要

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失明的第二大主要原因。视神经头的改变（ONH）Lamina Cribrosa（LC）中相关结缔组织的生物力学和病理重塑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（IOP）升高是青光眼唯一可改变的危险因素，尽管视力丧失可以在正常的IOP处发生。 IOP是一种压力，它会给ONH带来压力。机械应变和基础的细胞机械转导途径在onH的病理结缔组织重塑中发挥作用然而，青光眼中的巩膜仍然知之甚少。我们的中心假设是细胞水平应变，通过层流和巩膜组织刚度调节，驱动机械转移反应引起的 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，我们建议这些因素是青光眼易感性和在所有IOP级别上的进展。该提案的目标是1）确定生物力学因素有助于青光眼敏感性，2）确定机械诱导的细胞反应和青光眼中的结缔组织重塑。为了实现这一目标，我们将使用具有相同IOP端点的青光眼的单侧，诱导动物模型和人类供体眼睛。在AIM 1中，我们将确定青光眼的生物力学风险因素并确定重塑诱导的使用光学相干断层扫描的LC和巩膜的形态和机械反应改变和3D重建。我们还将确定慢性升高IOP对机械转导/ECM重塑途径在该模型中从该模型中收获的组织和细胞处于定义 IOP侮辱并将这种活动与硬化/ONH材料特性和轴突损失的变化相关。在AIM 2中，我们将确定动物模型中确定的途径是否受到类似调节的临床记录 - 验证了正常和青光眼的人类供体眼。在AIM 3中，我们将确定机械环境这可以使用眼睛特异性的多尺度3D计算模型刺激组织重塑。这些研究将导致鉴定生物力学因子和细胞机械传导途径，有助于巩膜/ONH ECM重塑和青光眼发病机理，目的是确定新的治疗靶标。