Interplay between intraocular and cerebrospinal fluid pressure effects on the optic nerve head in vivo

 描述（由申请人提供）：青光眼是致盲的主要原因，具有广泛的临床表现。虽然眼内压（IOP）被认为是青光眼最重要的危险因素，但对IOP敏感性的眼睛之间的差异仍然知之甚少。近年来，越来越多的证据表明青光眼的易感性与脑脊液压力（CSFP）的大小有关。据推测，这种关联是由于CSFP对视神经乳头（ONH）后部的作用力。我们的假设是IOP和CSFP都是ONH内生物力学环境的重要贡献者。在此框架下，IOP和CSFP之间的不平衡导致ONH组织变形，特别是筛板（LC），触发事件，如受损的轴浆流和血管灌注，以及星形胶质细胞激活，导致青光眼性视神经病变。因此，了解IOP和CSFP之间的相互作用对于了解IOP敏感性范围的机制至关重要。该项目的长期目标是确定IOP和CSFP对ONH的体内影响及其相互作用，在健康眼睛和暴露于慢性高眼压的眼睛中，并确定个体眼睛对这些压力的敏感性的最佳预测因子的特征。光学相干断层扫描（OCT）的进展使我们能够第一次获得ONH和LC在体内的详细可视化。在灵长类动物中，我们将控制IOP和CSFP，同时在多种压力组合下使用OCT对ONH区域进行成像。使用先进的图像处理，我们将确定全球，部门和局部压力引起的组织变形，包括拉伸，压缩和剪切。将使用组织形态测定法补充体内测量，其中参数在体内不可用。使用统计建模和第一原理生物力学，我们将开发一个机械模型的结构原因的个体眼睛敏感性IOP和CSFP。我们将确定IOP和CSFP的急性效应是否以及哪些是慢性IOP诱导的ONH变化（例如组织硬化和LC重塑）的良好预测因子，以及这些变化对ONH对IOP和CSFP敏感性的影响。该项目将提供有关ONH和LC体内生物力学的前所未有的信息。我们将能够根据眼睛的结构特征和对压力调制的生物力学反应来识别对压力高度敏感的眼睛特异性标记。结合实验和建模，我们将能够预测ONH参数，这些参数在传统环境中无法轻易测量，从而减少侵入性手术的使用。阐明IOP和CSFP之间的相互作用将有助于开发基于证据的预防和治疗干预措施，以降低青光眼发病率。

 DESCRIPTION (provided by applicant): Glaucoma is a leading cause of blindness with a wide range of clinical presentation. While intraocular pressure (IOP) is considered the most important risk factor for glaucoma, the variability between eyes in sensitivity to IOP is still poorly understood. In recent years, evidence has been accumulating of an association between the susceptibility to glaucoma and the magnitude of the cerebrospinal fluid pressure (CSFP). It has been speculated that this association is due to the forces of CSFP on the posterior aspect of the optic nerve head (ONH). Our hypothesis is that both IOP and CSFP are significant contributors to the biomechanical environment within the ONH. In this framework, an imbalance between IOP and CSFP results in deformations of the tissues of the ONH, particularly on the lamina cribrosa (LC), triggering events such as compromised axoplasmic flow and vascular perfusion, and astrocyte activation that contribute to glaucomatous optic neuropathy. Therefore, understanding the interplay between IOP and CSFP is central to understanding the mechanisms underlying the range of sensitivities to IOP. The long-term goal of this project is to determine the in-vivo effects of IOP and CSFP on the ONH and their interactions, in healthy eyes and in eyes exposed to chronic ocular hypertension, and to identify the characteristics that are best predictors of individual eye sensitivity to these pressures. Advances in optical coherence tomography (OCT) allows us, for the first time, to obtain detailed visualization of the ONH and the LC in-vivo. In primates, we will control the IOP and CSFP while imaging the ONH region with OCT in multiple pressure combinations. Using advanced image processing we will determine the global, sectoral and local pressure-induced tissue deformations, including stretch, compression and shear. Histomorphometry will be used to supplement the in-vivo measurements with parameters not available in vivo. Using statistical modeling and first-principles biomechanics we will develop a mechanistic model of the structural causes underlying individual eye sensitivity to IOP and CSFP. We will determine whether, and which, acute effects of IOP and CSFP are good predictors of chronic IOP-induced changes of the ONH (e.g. tissue stiffening and LC remodeling), and the effects that these changes have on the ONH sensitivity to IOP and CSFP. This project will provide unprecedented information on the in-vivo biomechanics of the ONH and LC. We will be able to identify eye-specific markers indicating eyes at heightened sensitivity to pressure according to their structural features, and biomechanical response to pressure modulation. Integrating experiments and modeling we will be able to predict ONH parameters that cannot be readily measured in conventional settings, reducing the use of invasive procedures. Clarifying the interactions between IOP and CSFP will enable development of evidence-based preventative and treatment interventions for reducing glaucoma morbidity.