Pressure Induced Dynamic 3D Changes in Lamina Cribrosa

描述(申请人提供)：青光眼是全球第二大致盲原因。虽然年龄和眼压(IOP)都是该病公认的危险因素，但其潜在的病理过程涉及视网膜神经节细胞(RGC)的加速死亡，这与进行性视力丧失有关。几十年来，视网膜神经节细胞的丢失主要是由于筛板的解剖和力学特征导致视神经头部(ONH)轴突的损伤，筛板是由胶原束组成的专门的ONH区，定义了轴突束离开眼睛的通道或毛孔。许多研究已经检测了眼压对筛板的影响，然而，包括固定、包埋和连续切片在内的组织学技术阻碍了直接研究眼压对胶原束组织和孔道/孔道大小的影响。共聚焦显微镜的发展为利用数字成像和重建算法动态评估组织的三维组织提供了一种新的、非侵入性的方法。重要的是，多光子共焦显微镜的最新进展是使用飞秒激光和高能脉冲，从胶原蛋白产生二次谐波(SH)信号，允许随着时间的推移非侵入性地直接对筛板进行光学成像。SH成像显微镜(SHIM)在ONH研究中的应用首次提供了检验一般假说的能力，即同一只眼的眼压升高会导致ONH胶原束的独立运动，从而导致筛板通道的扭曲和轴突束的压缩。为了验证这一假设，我们建议：1.开发一个实验舱，允许对新鲜的、未固定的人ONH加压，并允许Shim对其进行动态检查。2.确定压力变化对个体ONH筛板孔大小和形状的影响，作为深度和位置的函数。我们相信，我们使用SHIM可视化筛板的能力的成功将有力地支持对筛板的力学特性以及年龄和种族的后续影响的扩展研究，年龄和种族是进行性青光眼损害的重要预测因素。青光眼导致进行性视力丧失，并伴有视神经头结构的变化，通常被描述为拔火罐增加。年龄增大和眼压增加是青光眼进展的危险因素。我们建议使用一种新的技术来实现高分辨率、非侵入性的视神经头可视化。这项技术可以直接测量青光眼相关区域的结构变化，具有直接的临床意义和应用价值。

DESCRIPTION (provided by applicant): Glaucoma represents the second leading cause of blindness worldwide. While both age and intraocular pressure (IOP) are well-recognized risk factors for this disease, the underlying pathologic process involves accelerated death of retinal ganglion cells (RGC) that is associated with progressive loss of vision. For several decades loss of RGCs has been explained primarily by injury to axons in the optic nerve head (ONH) due to the anatomic and mechanical features of the lamina cribrosa, the specialized ONH zone comprised of collagen beams that define the channels or pores through which axon bundles exit the eye. Many studies have examined the effects of IOP on the lamina cribrosa; however, the histologic techniques used involving fixation, embedding and serial sectioning have precluded direct study of IOP effects on collagen beam organization and channel/pore size. The development of confocal microscopy, which optically sections tissue, has provided a new, non-invasive method for dynamically evaluating the 3-dimensional organization of tissue using digital imaging and reconstruction algorithms. Importantly, recent advances in multiphoton confocal microscopy using femtosecond lasers with high-energy pulses that generate second harmonic (SH) signals from collagen allows for direct optical imaging of the lamina cribrosa, non-invasively over time. The application of SH imaging microscopy (SHIM) to the study of the ONH provides for the first time the ability to test the general hypothesis that increasing intraocular pressure in the same eye results in the independent movement of ONH collagen beams leading to distortion of the lamina cribrosa channels and compression of the axon bundles. To test this hypothesis we propose to: 1. Develop an experimental chamber that will allow pressurizing fresh, unfixed human ONH and allow its dynamic examination by SHIM. 2. Determine the effects of changing pressure on lamina cribrosa pore size and shape in individual human ONH as a function of depth and location. We believe that demonstrated success in our ability to visualize the lamina cribrosa using SHIM will strongly support expanded study of the mechanical properties of lamina cribrosa and the consequent effects of age and ethnicity, important predictors of progressive glaucoma damage. Glaucoma causes progressive loss of vision accompanied by changes in the structure of the optic nerve head typically described as increased cupping. Advancing age and increasing eye pressure are risk factors for progression of glaucoma. We propose to use a new technology to visualize the optic nerve head with high resolution and non-invasively. This technique allows for direct measurement of the structural changes in the associated with glaucoma and has direct clinical relevance and application.