Dynamic and Static Autoregulation Impairment in the Optic Nerve Head of Glaucoma

青光眼视神经乳头的动态和静态自动调节损伤

• 批准号: 8500297
• 负责人: LIN WANG
• 金额: $ 34.88万
• 依托单位: LEGACY EMANUEL HOSPITAL AND HEALTH CENTER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-01 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8500297
• 关键词: Affect; American; Animals; Astrocytes; Autopsy; Axon; Axotomy; Blood Vessels; Blood capillaries; Blood flow; Brain Ischemia; Capillary Endothelial Cell; Chronic; Clinical; Contracts; Data; Detection; Development; Devices; Disease; Electrons; Experimental Models; Exposure to; Figs - dietary; Functional disorder; Glaucoma; Goals; Homeostasis; Human; Impairment; Injury; Investigation; Lasers; Measurement; Measures; Metabolic; Methods; Microscopic; Microspheres; Modeling; Monkeys; Nerve; Nerve Degeneration; Ocular Hypertension; Optic Disk; Optic Nerve; Optic Nerve Transections; Pathogenesis; Patients; Perfusion; Pericytes; Phase; Physiologic Intraocular Pressure; Process; Regional Blood Flow; Reporting; Retinal; Retinal Ganglion Cells; Role; Site; Staging; Techniques; Testing; Therapeutic Intervention; Tissues; Variant; Vascular Smooth Muscle; Vascular resistance; age related; base; blood flow measurement; capillary; clinical application; follow-up; in vivo; optic nerve disorder; pressure; reconstruction; response; retinal nerve fiber layer; therapeutic target; tissue slice preparation; vascular bed

Glaucoma is a disease characterized by irreversible damage of optic nerve affecting millions of Americans. Yet details of the underlying disease mechanism are still unclear. While recognizing the crucial role of intraocular pressure (IOP), autoregulation (AR) dysfunction has been proposed as a cause of circulatory aberrations in the optic nerve head (ONH) associated with glaucomatous optic neuropathy. Autoregulation in the normal ONH initiated by an ocular perfusion pressure change contains two phases: an initial dynamic phase (dAR) when vascular smooth muscles dilate and contract to adjust the vascular resistance in an attempt to return blood flow (BF) to its original level; and a later steady-state phase (sAR) when dynamic BF changes have equilibrated to a steady level. Due primarily to methodological limitations, most previous studies in human and experimental glaucoma have assessed only sAR and failed to detect AR dysfunction in the ONH. With a modified laser speckle flowgraphy device (LSFG) and newly established methods for measuring the dAR and sAR, this proposal will test the following central hypothesis: Chronic IOP elevation induces AR dysfunction in the ONH, which importantly contributes to the pathophysiology of glaucomatous ONH damage. This hypothesis will be tested in three Specific Aims. Specific Aim 1: To test the hypothesis that ONH dAR abnormalities develop early in the monkey experimental glaucoma model, that they precede sAR and bBF alterations and that they progress in parallel with clinical measures of ONH and RNFL structural disruption. Specific Aim 2: To test the hypothesis that the ONH AR abnormalities occurring in the monkey model of experimental glaucoma are a primary result of exposure to chronic IOP elevation rather than a secondary result of neurodegeneration. Specifically, we will test the prediction that AR abnormalities will not develop in two alternative, non-IOP-related, axonal injury models - optic nerve transection and intra-retinal laser axotomy. Specific Aim 3: the ONH tissues obtained from the animals studied in Specific Aims 1 and 2 will be used to carry out two postmortem histological studies: 3A) To assess regional BF in the monkey ONH using a state-of-the-art microsphere method and compare these measurements with the LSFG bBF estimates obtained immediately prior to sacrifice; and 3B) To test the hypothesis that AR dysfunction detected in vivo by LSFG is associated with derangement of the relationship between ONH astrocytes, lamina cribrosacytes and the blood vessels within the underlying laminar beams and peripapillary scleral beam insertions. In a follow up R01 proposal we expect to extend our investigation in: 1) clinical application by modifying the current techniques of dAR analysis to noninvasively so as to elicit a controlled ONH dAR response. 2) Characterization of ONH astrocytes and lamina cribrosacyte role in ONH AR using 3D electron microscopic reconstructions and fresh ONH tissue slice preparations. 3) To test the hypothesis of age-related alterations between astrocytes and capillary endothelial/pericytes in AR.

青光眼是一种以不可逆的视神经损伤为特征的疾病，影响数百万美国人。然而 潜在的疾病机制的细节仍然不清楚。在认识到的关键作用的同时 眼内压（IOP）、自动调节（AR）功能障碍已被认为是循环系统疾病的原因。 视神经乳头（ONH）畸变与青光眼性视神经病变相关。自动调节 在由眼灌注压变化引发的正常ONH中，包含两个阶段： 血管平滑肌扩张和收缩以调节血管阻力时， 尝试将血流（BF）恢复到其原始水平;以及当动态BF 变化已趋于稳定。由于方法上的限制，大多数人 对人类和实验性青光眼的研究仅评估了sAR，未能检测到AR功能障碍 在ONH。利用改进的激光散斑流图装置（LSFG）和新建立的方法， 通过测量dAR和sAR，本提案将检验以下中心假设：慢性IOP升高 在ONH中诱导AR功能障碍，这对脑胶质瘤的病理生理学有重要作用。 ONH损伤。这一假设将在三个具体目标中得到检验。具体目标1：检验假设 ONH dAR异常在猴实验性青光眼模型中早期出现， sAR和bBF改变，并且它们与ONH和RNFL的临床测量平行进展 结构性破坏。具体目的2：检验ONH AR异常发生在 实验性青光眼的猴模型是暴露于慢性IOP升高的主要结果， 而不是神经退化的继发结果具体来说，我们将测试AR异常的预测， 在两种替代的非IOP相关轴突损伤模型中不会发生-视神经横断和 视网膜内激光切断术特定目的3：从特定目的中研究的动物获得的ONH组织 目的1和2将用于进行两项死后组织学研究：3A）评估在组织中的区域BF， 猴子ONH使用国家的最先进的微球方法，并比较这些测量与 处死前即刻获得的LSFG bBF估计值;和3B）为了检验AR 通过LSFG在体内检测到的功能障碍与ONH与 星形胶质细胞、筛板细胞和下层板梁内的血管， 视乳头周围巩膜束插入。在后续的R 01提案中，我们希望在以下方面扩展我们的调查：1） 通过将当前的dAR分析技术修改为非侵入性的，以引起 控制ONH dAR反应。2)ONH星形胶质细胞和筛板细胞在ONH中的作用 AR使用3D电子显微镜重建和新鲜ONH组织切片制备。3)测试 AR中星形胶质细胞和毛细血管内皮细胞/周细胞之间年龄相关改变的假说。