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700万人因此而失明。 已有广泛的研究得出结论，原发性开角型青光眼(POAG)具有更高的 非洲裔和西班牙裔人口中的流行率。青光眼的力学理论 建立在机械损伤力作用于视神经导致视网膜丧失的假设之上 神经节细胞功能。虽然有证据表明筛板(LC)和 在青光眼存在的情况下，巩膜乳头周围(PS)重塑，这种重塑还没有得到广泛的研究 在某些高危人群(老年、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 在正常眼压下可发生开角型青光眼。目前的研究提案将调查两者之间的关系 PS和LC基质微观结构和力学性能之间的关系，试图确定这些 恋爱关系受种族/民族和年龄的影响。拟议工作的中心假设是 LC和PS的微观结构和力学性能的差异作为以下因素的函数存在 种族/民族和年龄。这些变化被认为是青光眼患病率较高的原因之一。 AD和HE人群与欧洲后裔(ED)人群的比较，独立于 眼压。 虽然LC和PS的细胞外基质微观结构已经被研究过，但如何 这种组织涉及这些组织的机械功能，目前尚不清楚。这是 这主要是因为几乎所有这种微观结构信息的量化都是由 依靠快速冷冻或将组织固定在包埋介质中的组织学研究(从而排除 同时进行机械表征)。我们最近开发了一种微型光学机械(MOMD) 能够同时测量非固定LC和PS的矩阵组织的装置，而这些 组织会发生机械变形。MOMD刺激胶原蛋白的二次谐波生成 双光子发射弹性蛋白的荧光，同时将眼睛后部组织暴露在 平面双轴或压力膨胀载荷。该项目的三个主要目标是找出差异 (作为种族/民族和年龄的函数)在1)不同眼压下人类LC的微结构组织； 2)人PS在不同眼压下的生物力学响应和微结构；3)生物力学 基于微结构的计算模拟眼球后部组织的环境。提供一个 详细说明与年龄和种族有关的LC和PS显微结构和机械性能的差异 属性可能为开发新的诊断和治疗方法提供独特的机会 机遇。

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.