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，全球有700万人因此失明。大量研究表明，原发性开角型青光眼（POAG）在非洲裔和西班牙裔人群中都有较高的患病率。青光眼的力学理论基于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的假设。虽然有证据表明，在青光眼存在时，筛层（LC）和乳头周围巩膜（PS）的细胞外基质会发生重塑，但这种重塑在某些高风险人群（老年人、非洲裔（AD）、西班牙裔（HE））中尚未得到广泛量化。这些群体的PS微观结构和力学性能的优先差异可能提供了在正常IOPs下发生POAG的机制。目前的研究计划将调查PS和LC基质微观结构和力学性能之间的关系，试图确定这些关系如何受到种族/民族和年龄的影响。提出的工作的中心假设是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。假设这些变化与眼压水平无关，与欧洲血统（ED）相比，AD和HE人群青光眼患病率较高。虽然LC和PS的细胞外基质微结构已经被研究过，但这种组织与这些组织的机械功能之间的关系目前还不清楚。这主要是由于几乎所有微观结构信息的量化都来自于组织学研究，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力学表征）。我们最近开发了一种微光机械（MOMD）装置，该装置能够同时测量非固定LC和PS组织在机械变形时的基质组织。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，同时将眼后组织暴露在平面双轴或压力膨胀载荷下。该项目的三个主要目标是确定以下方面的差异（作为种族/民族和年龄的函数）：1)不同IOPs下人类LC的微观结构组织；2)不同IOPs下人体PS的生物力学响应和微观结构；3)基于微结构的计算模拟眼后组织的生物力学环境。提供年龄和种族相关的LC和PS微观结构和力学性能差异的详细说明，可能为开发新的诊断和治疗机会提供独特的机会。

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.