Vascular dysfunction in glaucoma

摘要 青光眼是不可逆性失明的主要原因，其特征是青光眼的 视神经和视网膜神经节细胞(RGC)。青光眼损害可能是由隆起引起的 眼内压(IOP)，这可能会机械地对视神经施加压力，或者通过减少血流量，这是 会损害视神经的功能。降低眼压是青光眼唯一可用的治疗方法，但许多 尽管成功地降低了眼压，患者仍继续失去视力。与眼压无关的血管异常 可发生在青光眼患者，如血管痉挛和高血压。而血管功能障碍 与青光眼病理生理学有关，血流障碍是否可以作为靶点仍不确定。 进行干预。血流正常化是青光眼的一种引人注目的新治疗策略。 我们的实验室率先将多参数磁共振成像应用于高分辨率特定椎板的成像 啮齿动物和人类视网膜和视神经的解剖、定量血流和功能。这 包括视网膜、脉络膜和视神经头的体积血流MRI，以及弥散磁共振成像 测量视神经轴突的完整性。此外，我们有令人信服的初步数据表明，血液流动 在已建立的青光眼动物模型中减少，慢性轻度高氧治疗得到改善 青光眼的视网膜功能，支持血流障碍在青光眼发病机制中的作用。在此，我们 将利用我们的MRI方法进一步研究血管功能障碍在青光眼病理中的作用 评估使青光眼血流正常化的治疗方法。 这项建议的目标是将我们的新的眼部核磁共振方法用于已建立的小鼠青光眼。 模型：1)评估增加血流的新治疗策略是否可以预防青光眼 损害和2)评估降低眼压和正常化血流的联合治疗是否提供 防止青光眼进展的额外保护。我们的中心假设是血液流动失调 有助于青光眼的发病，因此治疗血流正常化可以防止损害和 最终在青光眼中保持视力。 这项研究的影响将是：1)对青光眼病理生理学的新见解和对 血流异常导致不可逆的结构和功能损害，ii)建立新的视网膜和视神经 神经MRI作为一种方法，提供关于体积血流量的独特的、临床相关的信息，以及iii) 建立青光眼血流正常化的创新治疗策略。这一事件的最终影响 工作将是预防青光眼导致的失明和视力丧失。

ABSTRACT Glaucoma, a leading cause of irreversible blindness, is characterized by progressive degeneration of the optic nerve and retinal ganglion cells (RGC). Glaucomatous damage might be caused either by elevated intraocular pressure (IOP), which could mechanically stress the optic nerve, or by reduced blood flow, which could impair function of the optic nerve. Lowering IOP is the only available treatment for glaucoma, but many patients continue to lose vision despite successful IOP reduction. Vascular abnormalities independent of IOP can occur in glaucoma patients, such as vasospasm and hypertension. While vascular dysfunction is associated with glaucoma pathophysiology, it remains uncertain whether blood flow impairment can be a target for intervention. Normalizing blood flow is a compelling novel treatment strategy for glaucoma. Our laboratory pioneered the application of multiparametric MRI to image high-resolution lamina-specific anatomy, quantitative blood flow, and function of the retina and optic nerve in rodents and in humans. This includes volumetric blood flow MRI of the retina, choroid, and optic nerve head, as well as diffusion MRI to measure optic nerve axonal integrity. Moreover, we have compelling preliminary data that blood flow is reduced in an established animal model of glaucoma and that chronic, mild hyperoxia treatment improves retinal function in glaucoma, supporting a role for blood flow impairment in glaucoma pathogenesis. Herein, we will utilize our MRI methods to further investigate the role of vascular dysfunction in glaucoma pathology by assessing a treatment to normalize blood flow in glaucoma. The goals of this proposal are to use our novel ocular MRI methods in an established mouse glaucoma model to: 1) evaluate whether a novel treatment strategy to increase blood flow can prevent glaucomatous damage and 2) evaluate whether combined treatments to lower IOP and normalize blood flow provide additional protection against glaucomatous progression. Our central hypothesis is that blood flow dysregulation contributes to glaucoma pathogenesis, so treatments to normalize blood flow could prevent damage and ultimately preserve vision in glaucoma. The impacts of this study will be i) novel insight into glaucoma pathophysiology and into the contribution of blood flow abnormalities to irreversible structural and functional damage, ii) establish novel retinal and optic nerve MRI as a method that provides unique, clinically relevant information on volumetric blood flow, and iii) establish an innovative treatment strategy for glaucoma of normalizing blood flow. The ultimate impact of this work would be to prevent blindness and vision loss due to glaucoma.