Structure and Biomechanics of the Human Optic Nerve Head

人类视神经头的结构和生物力学

• 批准号: 7887791
• 负责人: DONALD J BROWN
• 金额: $ 36.93万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-01 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7887791
• 关键词: 3-Dimensional; Accounting; Acoustics; Affect; Age; Aging; Arts; Biomechanics; Blindness; Collagen; Collagen Fibril; Coupled; Data; Development; Dimensions; Disease; Elastic Fiber; Elasticity; Elastin; Eye; Fluorescence; Functional disorder; Generations; Glaucoma; Goals; Health; Human; Individual; Inferior; Injury; Investigation; Lasers; Lateral; Lead; Maps; Measurement; Measures; Microscope; Microscopic; Microscopy; Monitor; Nose; Optic Disk; Optics; Pathology; Photons; Play; Predisposition; Primary Open Angle Glaucoma; Property; Public Health; Race; Radiation; Research Personnel; Resolution; Retinal Ganglion Cells; Risk Factors; Role; Signal Transduction; Structure; Technology; Testing; Time; Tissues; Ultrasonography; base; innovation; multidisciplinary; new technology; novel; pressure; public health relevance; regional difference; response; second harmonic; three dimensional structure; tomography; two-photon

DESCRIPTION (provided by applicant): Primary open angle glaucoma (POAG) represents a serious and growing health problem accounting for ~12% of global blindness. Studies have identified age, ancestral group (racial background), and intra- ocular pressure (IOP) as significant risk factors for the development and progression of POAG. Our long- range goal is to understand the relationship between these established risk factors and the responsive loss of retinal ganglia cells that characterizes this disease. Current wisdom proposes that the biomechanical properties of the optic nerve head (ONH) and lamina cribrosa (LC) play a critical role in defining the pathology of POAG. In preliminary studies, we have identified that regions of the LC susceptible to glaucomatous change (inferior, superior) contain less collagen and show more pressure-induced deformation (more compliant) than other regions of the LC (nasal and temporal). Building on these findings, the objective of this proposal is to define the 3 dimensional biomechanical properties of the ONH by microscopically reconstructing the structural components and biomechanical properties across the LC at a micron scale and relate these properties to POAG risk factors. Based on our preliminary studies we propose the following testable hypotheses:1) That there are regional differences in both the structure and pressure-induced deformation of the LC such that regions susceptible to early glaucomatous change have decreased collagen and increased deformation; 2) That the regional differences in LC structure and pressure-induced deformation increase with age and vary with ancestral group, such that older individuals and those with ancestries more susceptible to POAG will have greater structural changes and show greater pressure induced deformation; 3) That the regional differences in LC structure and pressure-induced deformation are directly related to differences in the 3 dimensional, microscopic elastic modulus such that regions of the LC most susceptible to glaucomatous damage (and related to age and ancestry) will have significant differences in the elastic modulus compared to other regions. To test these hypotheses, we have developed innovative, state of the art technologies to globally assess the three dimensional (3D) structure and biomechanical properties of the human ONH with high resolution. These technologies take advantage of known non-linear optical affects that occur when high intensity photons generated by ultrafast lasers interact with tissue. Using these novel technologies we propose to study ex vivo human eyes from normal individuals and different ancestries at varying ages by the following Specific Aims: 1) Dynamically map in 4 dimensions (time and space) IOP induced changes in collagen fibril and elastic fiber structure in ex vivo human ONH using an artificial pressure chamber and an ultrafast laser; 2) Three dimensionally reconstruct the ONH at high resolution (0.9 mm lateral and 2 mm axial) to volumetrically measure the regional changes in structure and relate these to the measured pressure induce deformations in the same eye; 3) Measure the regional (superior vs. inferior etc.) biomechanical properties of ex vivo human ONH to relate structure to the biomechanical properties and susceptibility to POAG. We expect that these investigations will provide new, and critically important, information concerning the biomechanical properties of the human ONH and provide a clearer understanding of the risk factors for POAG. PUBLIC HEALTH RELEVANCE: In this proposal, we will clarify the role of collagen and elastic components of the lamina cribrosa (LC) in the pathophysiology of axonal injury that occurs with aging and how it may be accelerated by increased IOP. We fully expect these data to lead to critically important information concerning the biomechanical properties of the human optic nerve head (ONH) and provide a clearer understanding of the risk factors for primary open angle glaucoma (POAG). To achieve our goal, we will use innovative, state of the art technologies based on ultrafast lasers that can produce two photon excited fluorescence for identifying elastin, second harmonic generated signals for identifying collagen and laser induced optical breakdown to probe the microscopic biomechanical properties using Acoustic Radiation Force Elastic Microscopy to globally assess the three dimensional structure and biomechanical properties of the ONH.

描述（由申请人提供）：原发性开角型青光眼 (POAG) 是一种严重且日益严重的健康问题，约占全球失明的 12%。研究已确定年龄、祖先群体（种族背景）和眼压（IOP）是 POAG 发生和进展的重要危险因素。我们的长期目标是了解这些已确定的危险因素与表征该疾病的视网膜神经节细胞的反应性丧失之间的关系。目前的观点认为，视神经乳头 (ONH) 和筛板 (LC) 的生物力学特性在定义 POAG 的病理学方面发挥着关键作用。在初步研究中，我们发现，与 LC 的其他区域（鼻区和颞区）相比，LC 中容易发生青光眼变化的区域（下、上）含有较少的胶原蛋白，并且表现出更多的压力引起的变形（更顺应）。基于这些发现，该提案的目标是通过在微米级显微镜下重建 LC 的结构组件和生物力学特性来定义 ONH 的 3 维生物力学特性，并将这些特性与 POAG 风险因素联系起来。 基于我们的初步研究，我们提出以下可检验的假设：1）LC的结构和压力引起的变形都存在区域差异，因此容易发生早期青光眼变化的区域胶原蛋白减少，变形增加； 2) LC结构和压力引起的变形的区域差异随着年龄的增长而增加，并随着祖先群体的不同而变化，因此年龄较大的个体和祖先更容易受到POAG影响的个体会出现更大的结构变化并表现出更大的压力引起的变形； 3) LC结构和压力引起的变形的区域差异与3维微观弹性模量的差异直接相关，因此LC最容易受到青光眼损伤的区域（与年龄和血统有关）与其他区域相比，其弹性模量将具有显着差异。 为了测试这些假设，我们开发了最先进的创新技术，以高分辨率对人类 ONH 的三维 (3D) 结构和生物力学特性进行全球评估。这些技术利用了超快激光产生的高强度光子与组织相互作用时发生的已知非线性光学效应。 利用这些新技术，我们建议通过以下具体目标，研究来自正常个体和不同年龄的不同血统的离体人眼：1)使用人工压力室和超快激光，动态绘制4个维度（时间和空间）IOP引起的离体人ONH中胶原纤维和弹性纤维结构的变化； 2) 以高分辨率（0.9 mm 横向和 2 mm 轴向）三维重建 ONH，以体积测量结构的区域变化，并将这些变化与测量的压力引起同一只眼睛的变形相关联； 3) 测量离体人 ONH 的区域（上等与下等）生物力学特性，以将结构与生物力学特性和对 POAG 的敏感性联系起来。 我们期望这些研究将提供有关人类 ONH 生物力学特性的新的且至关重要的信息，并提供对 POAG 风险因素的更清晰的了解。 公共健康相关性：在本提案中，我们将阐明胶原蛋白和筛板 (LC) 弹性成分在衰老过程中发生的轴突损伤的病理生理学中的作用，以及眼压增加如何加速轴突损伤。我们完全期望这些数据能够提供有关人类视神经头（ONH）生物力学特性的至关重要的信息，并提供对原发性开角型青光眼（POAG）危险因素的更清晰的了解。为了实现我们的目标，我们将使用基于超快激光器的创新、最先进的技术，这些技术可以产生用于识别弹性蛋白的双光子激发荧光、用于识别胶原蛋白的二次谐波生成信号以及激光诱导光学击穿，以使用声辐射力弹性显微镜来探测微观生物力学特性，从而全面评估 ONH 的三维结构和生物力学特性。