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

青光眼是一种以视神经不可逆转的损害为特征的疾病，影响着数百万美国人。还没有 潜在疾病机制的细节仍不清楚。在认识到 眼压(IOP)、自动调节(AR)功能障碍被认为是导致循环的原因之一 与青光眼视神经病变相关的视神经头(ONH)的异常。自动调节 在正常的ONH中，由眼部灌流引起的压力变化包括两个阶段：初始动态 血管平滑肌扩张和收缩以调节血管阻力的阶段(DAR 尝试将血流(BF)恢复到其原始水平；当动态BF时，进入较晚的稳态阶段(SAR 变化已经平衡到一个稳定的水平。主要由于方法上的限制，大多数以前的 对人类和实验性青光眼的研究只评估了SAR，没有检测到AR功能障碍 在医院里。用改进的激光散斑流动图装置(LSFG)和新建立的方法 通过测量DAR和SAR，这项提议将检验以下中心假设：慢性眼压升高 在ONH中诱导AR功能障碍，这在青光眼的病理生理学中起重要作用 哦，损坏。这一假设将在三个具体目标上得到检验。具体目标1：检验假设 ONH-DAR异常在猴子实验性青光眼模型的早期发展，它们先于 SAR和BBF的改变及其与ONH和RNFL临床指标的进展 结构性破坏。具体目标2：检验ONH AR异常发生在 猴子实验性青光眼模型是慢性眼压升高的主要结果 而不是神经退化的次要结果。具体地说，我们将测试AR异常 不会在两种替代的、非眼压相关的轴突损伤模型中发展-视神经横断术和视神经损伤 视网膜内激光轴突切断术。特定目标3：从特定研究的动物身上获得ONH组织 AIMS 1和AIMS 2将用于进行两项死后组织学研究：3A)评估 使用最先进的微球方法，并将这些测量结果与 在牺牲前立即获得的LSFG BBF估计；以及3B)检验AR的假设 LSFG在体内检测到的功能障碍与ONH之间的关系紊乱有关 星形胶质细胞、筛板细胞和下层板层梁内的血管 乳头状巩膜周梁植入。在后续的R01提案中，我们预计将在以下方面扩展我们的调查：1) 将现有的DAR分析技术改进为无创性的临床应用 受控的ONH DAR响应。2)ONH星形胶质细胞和筛板细胞在ONH中的作用 AR采用3D电子显微镜重建和新鲜的ONH组织切片制备。3)测试 变应性鼻炎星形胶质细胞与毛细血管内皮细胞/周细胞年龄相关性改变的假说。

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.