Extracelluar Matrix Organization and Biomechanics of the Lamina Cribrosa and Peri

描述（由申请人提供）：青光眼是全球第二大致盲原因，有700万人因此失明。有大量研究得出结论，原发性开角型青光眼（POAG）在非洲裔和西班牙裔人群中的患病率较高。青光眼的力学理论基于这样的假设，即作用于视神经的机械损伤力导致视网膜神经节细胞功能丧失。虽然有证据表明，筛板（LC）和视乳头周围巩膜（PS）的细胞外基质在青光眼的存在下重塑，但这种重塑尚未在某些高危人群（老年人，非洲裔（AD），西班牙裔（HE））中广泛量化。这些人群的PS微观结构和机械性能的优先差异可能提供了一种POAG在正常IOP下发生的机制。目前的研究计划将调查PS和LC基质微观结构和机械性能之间的关系，寻求确定这些关系如何受到种族/民族和年龄的影响。拟议工作的中心假设是，LC和PS的微观结构和力学性能的差异作为种族/民族和年龄的函数存在。假设这些变化在AD和HE人群中青光眼患病率高于欧洲血统（艾德）人群中发挥作用，与眼内压水平无关。 虽然之前已经研究了LC和PS的细胞外基质微观结构，但目前尚不清楚这种组织与这些组织的机械功能之间的关系。这主要是因为几乎所有的微观结构信息的量化都来自组织学研究，这些研究依赖于快速冷冻或将组织固定在包埋介质中（因此排除了同时进行的机械表征）。我们最近开发了一种微光学机械（MOMD）设备，它能够同时测量矩阵组织的未固定的LC和PS，而这些组织进行机械变形。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或压力膨胀负荷。该项目的三个主要目的是确定以下方面的差异（作为人种/种族和年龄的函数）：1）不同IOP下人类LC的微观结构组织; 2）不同IOP下人类PS的生物力学响应和微观结构;以及3）使用基于微观结构的计算模拟的后眼组织的生物力学环境。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，可能为开发新的诊断和治疗机会提供独特的机会。 公共卫生相关性：青光眼是世界范围内第二大致盲原因，据估计，2010年将影响6000万人，到2020年将影响8000万人。视神经附近组织的组成和性质的改变可能使某些高危人群易患原发性开角型青光眼，即使在相对低的眼内压下也是如此。识别这些变化可能最终导致改善这种疾病的诊断和治疗。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: As the second leading cause of blindness worldwide, glaucoma is estimated to affect 60 million people in 2010 and will affect 80 million by 2020. Alterations in the makeup and properties of the tissues near the optic nerve may predispose certain high risk populations to primary open angle glaucoma, even at relatively low intraocular pressures. Identification of such changes may eventually lead to improved diagnosis and treatment of this disease.