Cross-species vascular anatomy and sensitivity to intraocular pressure in glaucoma

青光眼的跨物种血管解剖学和对眼压的敏感性

• 批准号: 10493356
• 负责人: Tatjana Claudia Jakobs
• 金额: $ 49.76万
• 依托单位: MASSACHUSETTS EYE AND EAR INFIRMARY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-30 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10493356
• 关键词: 3-Dimensional; Acute; Address; Affect; Anastomosis - action; Anatomy; Angiography; Architecture; Area; Automobile Driving; Autopsy; Basement membrane; Biomechanics; Blindness; Blood Vessels; Blood capillaries; Blood flow; Characteristics; Chronic; Clinical; Collagen; Connective Tissue; Contralateral; Data; Deposition; Development; Diffuse; Disease; Dyes; Eye; Fluorescent Dyes; Glaucoma; Histologic; Human; Image; Immunohistochemistry; In Situ; Injections; Ischemia; Knowledge; Label; Link; Maps; Measurement; Measures; Mechanics; Modeling; Monkeys; Morphology; Mus; Neuropathy; Open-Angle Glaucoma; Optic Disk; Optic Nerve; Optical Coherence Tomography; Pathologic; Pathology; Pattern; Perfusion; Physiologic Intraocular Pressure; Predisposition; Primates; Property; Resolution; Risk Factors; Role; Scotoma; Shelter facility; Solid; Source; Stenosis; Structure; Techniques; Testing; Time; Tissues; Variant; Vascular Diseases; Vascular blood supply; Weight-Bearing state; axon injury; central retinal artery; clinical imaging; clinical phenotype; ex vivo imaging; experimental study; high intraocular pressure; imaging modality; in vivo; insight; model building; nerve injury; relating to nervous system

SUMMARY Vascular dysfunction, with or without elevated intraocular pressure (IOP), is believed to be an important risk factor in glaucoma and other neuropathies. However, the link between vascular dysfunction and the mechanisms leading to the characteristic visual field defects in glaucoma is not fully understood. This is partly due to the lack of a solid quantitative understanding of the 3D architecture of the vasculature of the optic nerve head (ONH), its anatomical relationship with the load-bearing connective tissues, and how it is affected by IOP. Our overarching hypothesis is that features of the vasculature and its relationship with the connective tissues predispose certain ONH regions to compromised perfusion and that this susceptibility is amplified by elevated IOP. To test this hypothesis, we will sequentially collect in vivo, ex vivo, and histological 3D morphological and biomechanical data on vascular and connective tissues of the ONH in normal eyes and in eyes with experimental glaucoma (EG). We will focus on the critical lamina cribrosa (LC) region in three species: human, monkey (closest model to human, collagenous LC), and mouse (most used model, no collagenous LC). In Aim 1, we will map in 3D the vasculature and connective tissues of the ONHs of humans, monkeys, and mice, and analyze these maps quantitatively including by watershed analysis. We predict that zones of visual loss in early glaucoma will correspond to regions with the most vulnerable vascular supply, e.g., sparse capillaries with low connectivity and low perfusion redundancy. We postulate that, in primates, not all LC beams have a capillary, and conversely, that some capillaries are not within a robust collagen-rich beam. We will also address the clinically important question to which extent in vivo OCT angiography visualizes the smaller or deeper vessels inside the ONH. In Aim 2, we will perform ex vivo inflation tests on monkey and mouse eyes to quantify the effects of acute IOP elevation on vessel perfusion and biomechanics, and the LC beams support. Our preliminary data suggests that “unprotected” vessels may be particularly vulnerable to mechanical distortion, which could, in turn, affect blood flow. In Aim 3, we will characterize the effects of chronic IOP elevation on vessels and beams. Specifically, we will compare eyes before and after chronic IOP elevation (EG), and with the contralateral control. This will allow us to discern characteristics that pre-dispose an eye to glaucoma from those that are the result of the disease. We will test the hypothesis that the patterns of vessel sensitivity to elevated IOP in mice (that have only a glial lamina) are different from those in primates. Combining multiple imaging modalities across the same ONHs in three species will provide cross-verification of the techniques, and deeper insights into the role of LC collagenous beams supporting the ONH vasculature under normal and elevated IOP. These experiments will help identifying ONH features that predict susceptibility to neural injury and vision loss.

摘要 血管功能障碍，无论是否伴有眼压升高，都被认为是一个重要的危险因素。 导致青光眼和其他神经性疾病的因素。然而，血管功能障碍与发病机制之间的联系 导致青光眼特征性视野缺陷的机制尚不完全清楚。这部分是由于缺乏 对视神经头(ONH)血管系统的3D构筑有坚实的定量理解，其 与负重结缔组织的解剖关系以及眼压对其的影响。我们最重要的是 假说是血管系统的特征及其与结缔组织的关系易患 这种敏感性会因眼压升高而放大。 为了验证这一假设，我们将依次收集体内、体外和组织学3D形态和 ONH正常眼和实验性眼血管结缔组织的生物力学数据 青光眼(EG)。我们将集中在三个物种的关键筛板(LC)区域：人、猴子 (最接近人类的模型，胶原性LC)和小鼠(最常用的模型，没有胶原性LC)。在目标1中，我们将 在3D中绘制人、猴子和小鼠的ONH的血管系统和结缔组织图，并分析 这些地图在数量上，包括通过流域分析。我们预测早期青光眼的视力丧失区域 将对应于血管供应最脆弱的区域，例如连接程度较低的稀疏毛细血管 和低灌注冗余度。我们假设，在灵长类动物中，并不是所有的LC梁都有毛细血管，相反， 一些毛细血管不在强健的富含胶原蛋白的光束内。我们还将讨论临床上重要的 在体内OCT血管造影术能在多大程度上显示ONH内更小或更深的血管。在……里面 目的2，我们将在猴子和小鼠的眼睛上进行体外充气测试，以量化急性眼压的影响 血管灌注和生物力学方面的提升，以及LC梁的支撑。我们的初步数据表明 “无保护”的血管可能特别容易受到机械变形的影响，这反过来又会影响血液。 流。在目标3中，我们将描述慢性眼压升高对血管和眼梁的影响。具体来说，我们 比较慢性眼压升高(EG)前后及与对侧对照眼的差异。这将允许 我们需要区分导致青光眼的特征和由疾病引起的特征。 我们将测试这一假设，即血管对高眼压的敏感模式在小鼠(只有胶质细胞)中 叶片)与灵长类动物的不同。在同一ONH中合并多个成像设备 三个物种将提供技术的交叉验证，并更深入地了解LC胶原蛋白的作用 在眼压正常和升高的情况下支撑ONH血管系统的光束。这些实验将有助于识别 ONH功能可预测神经损伤和视力丧失的易感性。