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

 描述(申请人提供)：青光眼是导致失明的主要原因，具有广泛的临床表现。虽然眼压(IOP)被认为是青光眼最重要的危险因素，但不同眼睛对IOP的敏感度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，这种联系是由于CSFP对视神经头(ONH)后方的力所致。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。在这个框架中，眼压和CSFP之间的失衡导致ONH的组织变形，特别是在筛板(LC)上，触发了一些事件，如轴浆流动和血管灌流受损，以及导致青光眼视神经病变的星形胶质细胞激活。因此，了解IOP和CSFP之间的相互作用对于理解IOP敏感性范围的潜在机制至关重要。该项目的长期目标是确定眼压和CSFP对健康眼和慢性高眼压暴露眼的ONH及其相互作用的体内影响，并确定最能预测个体眼睛对这些压力敏感性的特征。光学相干层析成像(OCT)的进展使我们第一次能够在活体内获得ONH和LC的详细可视化。在灵长类动物中，我们将控制眼压和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技术，我们将确定整体、部门和局部压力引起的组织变形，包括拉伸、压缩和剪切。组织形态计量学将用于补充体内测量的参数，这些参数在体内无法获得。利用统计建模和第一原理生物力学，我们将开发一个个体眼睛对IOP和CSFP敏感的结构原因的力学模型。我们将确定眼压和CSFP的急性效应是否以及哪些是慢性IOP引起的ONH变化(如组织硬化和LC重塑)的良好预测指标，以及这些变化对ONH对IOP和CSFP的敏感性的影响。该项目将为ONH和LC的体内生物力学提供前所未有的信息。我们将能够根据眼睛的结构特征和对压力调节的生物力学反应来识别眼睛特有的标志，表明眼睛对压力的高度敏感性。结合实验和建模，我们将能够预测在传统设置下不容易测量的ONH参数，从而减少侵入性程序的使用。澄清眼压和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，以减少青光眼的发病率。

 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.