Extracelluar Matrix Organization and Biomechanics of the Lamina Cribrosa and Peripapillary Sclera in Populations at High Risk for Primary Open Angle Glaucoma

项目摘要 青光眼是全球第二大致盲原因，有700万人因此失明。 已经有广泛的研究得出结论，原发性开角型青光眼（POAG）具有较高的 非洲裔和西班牙裔人群的患病率。青光眼的机械理论 依赖于这样的假设，即作用于视神经的机械损伤力导致视网膜神经节细胞的损失。 神经节细胞功能虽然有证据表明筛板（LC）的细胞外基质和 青光眼患者的视乳头周围巩膜（PS）重塑， 在某些高风险人群（老年人，非洲裔（AD），西班牙裔（HE））中进行量化。优惠 这些群体的PS微观结构和机械性能的差异可能提供了一种机制， POAG可以在正常的IOP下发生。目前的研究计划将调查 PS和LC基质的微观结构和力学性能之间的关系，试图确定这些 关系受到种族/民族和年龄的影响。拟议工作的中心假设是， LC和PS的微观结构和机械性能的差异是以下因素的函数 种族/民族和年龄。这些变化被假设在青光眼的高患病率中起作用， AD和HE人群与欧洲血统（艾德）人群相比， 眼压 虽然以前已经研究了LC和PS的细胞外基质微观结构， 这种组织与这些组织的机械功能有关，目前尚不清楚。这是 这主要是因为几乎所有的微观结构信息的量化都来自于 组织学研究依赖于快速冷冻或将组织固定在包埋介质中（从而排除 同时机械表征）。我们最近开发了一种微光机械（MOMD） 一种能够同时测量未固定LC和PS的基质组织的装置， 组织经历机械变形。MOMD激发胶原蛋白的二次谐波产生 和弹性蛋白的双光子发射荧光，同时将后眼组织暴露于 平面双轴载荷或压力膨胀载荷。该项目的三个主要目标是确定差异 (as种族/民族和年龄的函数）1）不同IOP下人LC的微观结构组织; 2)不同IOP下人PS的生物力学响应和微观结构;以及3） 使用基于微结构的计算模拟的后眼组织的环境。提供 详细说明年龄和种族相关的LC和PS微观结构和机械性能差异 这些性质可能为开发新的诊断和治疗提供独特的机会 机会

Project Summary Glaucoma is the 2nd leading cause of blindness worldwide, as 7 million people are blind from this condition. There have been extensive studies concluding that primary open angle glaucoma (POAG) has a higher prevalence in populations of both African descent and Hispanic ethnicity. The mechanical theory of glaucoma rests on the assumption that mechanical damage forces acting on the optic nerve cause a loss of retinal ganglion cell function. While there is evidence that the extracellular matrix of the lamina cribrosa (LC) and peripapillary sclera (PS) remodel in the presence of glaucoma, this remodeling has not been extensively quantified in certain higher risk populations (aged, African Descent (AD), Hispanic Ethnicity (HE)). Preferential differences in the PS microstructure and mechanical properties of these populations may provide a mechanism by which POAG can occur at normal IOPs. The current research proposal will investigate the relationship between PS and LC matrix microstructure and mechanical properties, seeking to identify how these relationships are affected by race/ethnicity and age. The central hypothesis of the proposed work is that differences in the microstructure and mechanical properties of the LC and PS exist as a function of race/ethnicity and age. These changes are hypothesized to play a role in the higher prevalence of glaucoma in populations of AD and HE compared with those of European Descent (ED), independent of the level of intraocular pressure. While the extracellular matrix microstructures of the LC and PS have been investigated previously, how such organization relates to the mechanical function of these tissues is not currently understood. This is primarily due to the fact that nearly all quantification of this microstructural information has resulted from histological studies which rely on snap freezing or fixing the tissue in an embedding medium (thus precluding simultaneous mechanical characterization). We have recently developed a micro-optomechanical (MOMD) device which is capable of simultaneously measuring the matrix organization of unfixed LC and PS while these tissues undergo mechanical deformations. The MOMD excites the second harmonic generation of collagen and the two-photon emitted fluorescence of elastin while simultaneously exposing posterior ocular tissues to either planar biaxial or pressure-inflation loads. The three primary aims of this project are to identify differences (as a function of race/ethnicity and age) in 1) the microstructural organization of the human LC at various IOPs; 2) the biomechanical response and microstructure the human PS at various IOPs; and 3) the biomechanical environment of posterior ocular tissues using microstructurally-based computational simulations. Providing a detailed account of age and ethnicity associated differences in LC and PS microstructure and mechanical properties may provide a unique opportunity for the development of novel diagnosis and treatment opportunities.