Manganese-enhanced MRI Studies of Retinal Neovascularization

视网膜新生血管的锰增强 MRI 研究

• 批准号: 7237746
• 负责人: BRUCE A. BERKOWITZ
• 金额: $ 18.81万
• 依托单位: WAYNE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-05-01 至 2009-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7237746
• 关键词: Address; Appearance; Biological Markers; Blindness; Blood Vessels; Calcium; Cells; Condition; Contrast Media; Dark Adaptation; Development; Diabetes Mellitus; Diabetic Retinopathy; Disease; Electroretinography; Energy Metabolism; Eye; Functional Magnetic Resonance Imaging; Functional disorder; Histology; Homeostasis; Ions; Knowledge; Light; Link; Magnetic Resonance Imaging; Manganese; Measures; Metabolic; Methods; Metric; Modeling; Mus; Neuronal Dysfunction; Neurons; Newborn Infant; Pattern; Play; Premature Birth; Rattus; Research; Resolution; Retina; Retinal; Retinal Diseases; Retinal Neovascularization; Retinopathy of Prematurity; Rodent; Rodent Model; Role; Site; Specificity; Testing; Vision; awake; in vivo; innovation; manganese chloride; mouse model; neovascularization; novel; retina blood vessel structure; uptake

DESCRIPTION (provided by applicant): Energy metabolism in all mammalian retinal cells is linked with demand for ions such as calcium. This metabolic-ion demand axis plays a central role in normal retinal function and hence healthy vision. Loss of vision and blindness are associated with the appearance of retinal neovascularization (NV) in diseases such as retinopathy of prematurity (ROP) and diabetic retinopathy. The pathophysiology associated with retinal NV is not well understood, although neuronal dysfunction and perturbed ion homeostasis have both been suggested as important factors. It is not yet known if abnormal ion demand occurs before the appearance of retinal NV and in retinal regions that give rise to retinal NV. These temporal and spatial knowledge gaps can not be addressed at present because current methods lack either spatial specificity (e.g., electroretinogram) or the ability to provide functional metrics of ion demand in vivo (histology). We propose a novel method to non-invasively measure retinal layer-specific ion demand that can also be applied in experimental rodent models of NV. This method, manganese-enhanced MRI (MEMRI), takes advantage of the facts that manganese (Mn2+) ion is a surrogate biomarker for various ions including calcium, and is a strong MRI contrast agent. We have validated that known retinal layer-specific changes in neuronal function / ion demand during light and dark adaptation can be robustly measured by high resolution MEMRI following systemic administration of a non-toxic amount of MnCl2 to awake rodents. Our overlying hypothesis is that the appearance of retinal NV will be temporally and spatially linked with abnormal neuronal function, as assessed by perturbed manganese uptake. Aim 1: To test the prediction that retinal NV in rat and mouse models is linked with abnormal Mn2+ uptake (indicative of perturbed ion demand) at the border of vascular and avascular retina (i.e., the site of retinal NV). The results of this innovative research will help clarify whether or not abnormal ion demand plays an important role in the development of preretinal NV. The novel methods in this application will also contribute to the advancement of functional MRI for the study of retinal diseases. The results of this innovative research will help clarify whether or not abnormal ion demand plays an important role in the development of preretinal neovascularization, a major cause of vision loss and blindness in premature births and diabetes. The novel methods in this application will also contribute to the advancement of functional MRI for the study of retinal diseases.

描述（由申请人提供）：所有哺乳动物视网膜细胞的能量代谢都与钙等离子的需求有关。这种代谢离子需求轴在正常视网膜功能以及健康视力中发挥着核心作用。视力丧失和失明与早产儿视网膜病变 (ROP) 和糖尿病视网膜病变等疾病中视网膜新生血管 (NV) 的出现有关。尽管神经元功能障碍和离子稳态紊乱都被认为是重要因素，但与视网膜 NV 相关的病理生理学尚不清楚。目前尚不清楚异常离子需求是否出现在视网膜 NV 出现之前以及引起视网膜 NV 的视网膜区域。这些时间和空间知识差距目前无法解决，因为当前的方法缺乏空间特异性（例如视网膜电图）或提供体内离子需求功能指标（组织学）的能力。我们提出了一种非侵入性测量视网膜层特定离子需求的新方法，该方法也可应用于 NV 实验啮齿动物模型。这种方法，即锰增强 MRI (MEMRI)，利用了锰 (Mn2+) 离子是包括钙在内的各种离子的替代生物标志物的事实，并且是一种强 MRI 造影剂。我们已经验证，在对清醒的啮齿动物全身施用无毒量的 MnCl2 后，可以通过高分辨率 MEMRI 可靠地测量明适应和暗适应过程中神经元功能/离子需求的已知视网膜层特异性变化。我们的首要假设是，视网膜 NV 的出现在时间和空间上与神经元功能异常有关，通过锰摄取紊乱进行评估。目标 1：测试大鼠和小鼠模型中视网膜 NV 与血管和无血管视网膜边界（即视网膜 NV 部位）异常 Mn2+ 摄取（表明离子需求扰动）相关的预测。这项创新研究的结果将有助于阐明异常离子需求是否在视网膜前 NV 的发展中发挥重要作用。该应用中的新方法也将有助于促进功能性 MRI 在视网膜疾病研究中的进步。这项创新研究的结果将有助于阐明异常离子需求是否在视网膜前新生血管形成中发挥重要作用，视网膜前新生血管形成是早产和糖尿病视力丧失和失明的主要原因。该应用中的新方法也将有助于促进功能性 MRI 在视网膜疾病研究中的进步。