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: 7988489
• 负责人: LIN WANG
• 金额: $ 38.25万
• 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/7988489
• 关键词: Affect; American; Animals; Arts; Astrocytes; Autopsy; Axon; Axotomy; Blood Vessels; Blood capillaries; Blood flow; Brain Ischemia; Capillary Endothelial Cell; Chronic; Clinical; Complement component C1s; 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; public health relevance; reconstruction; response; retinal nerve fiber layer; therapeutic target; tissue slice preparation; vascular bed

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: This project seeks evidence of autoregulation (AR) dysfunction in the optic nerve head and its role in pathogenesis of glaucoma as well as to develop and assess a method for its clinical detection. These developments will make the detection of AR dysfunction in human ocular hypertensive and glaucoma patients a credible goal and the presence of AR dysfunction a therapeutic target for the treatment of the disease.

描述（申请人提供）：青光眼是一种以视神经不可逆转损伤为特征的疾病，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。在认识到眼内压（IOP）的关键作用的同时，自动调节（AR）功能障碍已被认为是与青光眼性视神经病变相关的视神经乳头（ONH）循环畸变的原因。由眼灌注压变化引发的正常ONH中的自动调节包含两个阶段：初始动态阶段（dAR），此时血管平滑肌扩张和收缩以调节血管阻力，试图使血流（BF）返回到其原始水平;以及后期稳态阶段（sAR），此时动态BF变化已平衡到稳定水平。主要由于方法上的局限性，大多数先前在人类和实验性青光眼中的研究仅评估了sAR，未能检测到ONH中的AR功能障碍。利用改良的激光散斑血流图装置（LSFG）和新建立的测量dAR和sAR的方法，该提议将测试以下中心假设：慢性IOP升高诱导ONH中的AR功能障碍，这对青光眼ONH损伤的病理生理学有重要贡献。这一假设将在三个具体目标中得到检验。具体目标1：为了检验ONH dAR异常在猴实验性青光眼模型中早期发展的假设，即它们先于sAR和bBF改变，并且它们与ONH和RNFL结构破坏的临床测量平行进展。具体目标二：为了检验实验性青光眼猴模型中发生的ONH AR异常是暴露于慢性IOP升高的主要结果而不是神经变性的次要结果的假设。具体而言，我们将在两种替代的非IOP相关的轴突损伤模型-视神经横断和视网膜内激光轴突切开术中测试AR异常不会发展的预测。具体目标3：从特定目的1和2中研究的动物获得的ONH组织将用于进行两项死后组织学研究：3A）使用最先进的微球方法评估猴ONH中的局部BF，并将这些测量结果与处死前即刻获得的LSFG bBF估计值进行比较;和3B）为了检验通过LSFG在体内检测到的AR功能障碍与ONH星形胶质细胞之间关系的紊乱相关的假设，筛板和下层板梁和视乳头周围巩膜梁插入内的血管。在后续的R 01提案中，我们期望在以下方面扩展我们的研究：1）通过将当前的dAR分析技术修改为非侵入性的，以引起受控的ONH dAR反应，从而将我们的研究扩展到临床应用。2)使用3D电子显微镜重建和新鲜ONH组织切片制备表征ONH星形胶质细胞和筛板细胞在ONH AR中的作用。3)检验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变化的假设。 公共卫生关系：本项目旨在寻找视神经乳头自身调节功能障碍的证据及其在青光眼发病机制中的作用，并开发和评估其临床检测方法。这些发展将使检测人类高眼压和青光眼患者中的AR功能障碍成为一个可信的目标，并且AR功能障碍的存在成为治疗该疾病的治疗靶点。