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（由申请人提供）：青光眼是一种以视神经不可逆损伤为特征的疾病，影响数百万美国人。然而，潜在疾病机制的细节仍不清楚。在认识到眼内压（IOP）的关键作用的同时，自动调节（AR）功能障碍被认为是与青光眼视神经病变相关的视神经头（ONH）循环异常的原因。由眼灌注压变化引起的正常ONH的自动调节包括两个阶段：初始动态阶段（dAR），血管平滑肌扩张和收缩以调节血管阻力，试图将血流（BF）恢复到原始水平；当动态BF变化平衡到稳定水平时，随后的稳态阶段（sAR）。由于方法学的限制，大多数先前的人类和实验性青光眼研究仅评估了sAR，未能检测到ONH的AR功能障碍。本研究利用改进后的激光散斑血流仪（LSFG）和新建立的测量dAR和sAR的方法，验证以下中心假设：慢性IOP升高导致ONH AR功能障碍，这对青光眼ONH损伤的病理生理有重要作用。这一假设将在三个具体目标中进行测试。具体目的1：验证ONH dAR异常在猴子实验性青光眼模型中早期出现的假设，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并行发展。特异性目的2：验证猴实验性青光眼模型中ONH AR异常是暴露于慢性IOP升高的主要结果，而不是神经退行性变的继发结果。具体来说，我们将在视神经横断和视网膜内激光轴突切开术两种非视神经相关的轴突损伤模型中测试AR异常不会发生的预测。具体目标3：从具体目标1和2中研究的动物身上获得的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子ONH的区域BF，并将这些测量结果与献祭前立即获得的LSFG bBF估计进行比较；和3B)验证LSFG在体内检测到的AR功能障碍与ONH星形细胞、层状滤泡细胞与底层层状梁和乳头周围巩膜梁插入处血管之间关系的紊乱有关。在后续的R01提案中，我们希望扩展我们的研究：1)通过修改当前的dAR分析技术到无创的临床应用，从而引起可控的ONH dAR反应。2)利用三维电镜重建和新鲜ONH组织切片制备表征ONH星形胶质细胞和层状滤泡细胞在ONH AR中的作用。3)验证AR中星形胶质细胞和毛细血管内皮细胞/周细胞之间的年龄相关改变假说。