Vascular dysfunction in glaucoma

青光眼的血管功能障碍

• 批准号: 10364260
• 负责人: Eric Raymond Muir
• 金额: $ 39.88万
• 依托单位: STATE UNIVERSITY NEW YORK STONY BROOK
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10364260
• 关键词: Anatomy; Animal Model; Axon; Blindness; Blood Pressure; Blood Vessels; Blood flow; Choroid; Chronic; Combined Modality Therapy; Data; Diffusion Magnetic Resonance Imaging; Electroretinography; Eye; Functional disorder; Future; Glaucoma; Goals; Histologic; Histology; Human; Hyperoxia; Hypertension; Imaging Techniques; Impairment; Intervention; Knowledge; Laboratories; Laser Speckle Imaging; Magnetic Resonance Imaging; Measurement; Measures; Mechanical Stress; Methods; Microspheres; Modeling; Mus; Optic Disk; Optic Nerve; Optical Coherence Tomography; Outcome Measure; Pathogenesis; Pathology; Patients; Perfusion; Physiologic Intraocular Pressure; Placebos; Retina; Retinal Ganglion Cells; Rodent; Role; Testing; Treatment Protocols; Vascular Diseases; Vasodilator Agents; Vasospasm; Vision; Visual impairment; Work; clinically relevant; clinically significant; density; functional outcomes; hemodynamics; high resolution imaging; imaging modality; improved; innovation; insight; novel; novel therapeutic intervention; optical imaging; preservation; prevent; retinal imaging; sildenafil; treatment strategy; vascular abnormality

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.

摘要 青光眼是导致不可逆失明的主要原因，其特征在于视网膜的进行性变性。 视神经和视网膜神经节细胞（RGC）。青光眼损害可能是由于 眼内压（IOP），这可能会机械压迫视神经，或通过减少血流， 可能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 尽管成功降低了IOP，患者仍继续丧失视力。与IOP无关的血管异常 青光眼患者可发生血管痉挛和高血压等。虽然血管功能障碍是 与青光眼的病理生理学相关，血流障碍是否可以作为目标仍然不确定 进行干预。正常化血流是一种引人注目的青光眼新治疗策略。 我们的实验室率先应用多参数MRI成像高分辨率椎板特异性 解剖学，定量血流，以及啮齿动物和人类视网膜和视神经的功能。这 包括视网膜、脉络膜和视神经乳头的容积血流MRI，以及弥散MRI， 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， 在已建立的青光眼动物模型中， 视网膜功能在青光眼中的作用，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学中的作用， 评估使青光眼中的血流正常化的治疗。 本提案的目的是使用我们的新的眼部MRI方法在一个既定的小鼠青光眼 模型：1）评估增加血流量的新治疗策略是否可以预防脑卒中 2）评估降低IOP和使血流正常化的联合治疗是否提供了 额外的保护，防止昏迷的进展。我们的中心假设是血流失调 有助于青光眼发病机制，因此使血流正常化的治疗可以防止损害， 最终保护青光眼的视力。 这项研究的影响将是i）对青光眼病理生理学的新见解和对青光眼的贡献。 血流异常导致不可逆的结构和功能损伤，ii）建立新的视网膜和视神经系统， 神经MRI作为一种提供关于体积血流的独特的临床相关信息的方法，以及iii） 建立了一种使血流正常化的青光眼创新治疗策略。这件事的最终影响 工作将是预防青光眼引起的失明和视力丧失。