Optic Nerve Head Mechanobiology in Glaucoma

摘要 在发达国家，青光眼是导致失明的第二大原因。视神经头的改变 筛板相关结缔组织的生物力学和病理重塑 和巩膜在青光眼视网膜神经节细胞轴突损伤和视力丧失中起重要作用。 眼压升高是青光眼的唯一可改变的危险因素，尽管视力丧失可能 发生在正常眼压时。眼压是一种会给ONH带来压力的压力。机械应变和压力的作用 细胞机械转导通路在ONH病理性结缔组织重塑中的作用 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级的菌株， 受板层和巩膜组织硬度的调节，驱动机械转导反应，从而导致 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 所有眼压水平的进展。这项建议的目标是1)确定生物力学因素， 有助于青光眼的易感性，以及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眼压终点和人类供体的单侧、可诱导的青光眼动物模型。 眼睛。在目标1中，我们将确定青光眼的生物力学危险因素，并确定青光眼诱发的重塑。 光学相干断层扫描对LC和巩膜的形态和力学响应的影响 和3D重建。我们还将确定慢性高眼压对 从该模型中获得的组织和细胞中的机械转导/细胞外基质重塑通路 眼压侮辱这种活动，并将其与巩膜/ONH材料性质和轴突丢失的变化相关联。在目标2中， 我们将确定动物模型中确定的通路是否为类似的受监管的临床记录- 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 这使用眼睛特定的、多比例的眼睛3D计算模型来刺激组织重建。这些 研究将导致确定生物力学因素和细胞机械转导途径， 有助于巩膜/ONH ECM重塑和青光眼发病机制，目的是确定新的 治疗靶点。

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.