Manganese-enhanced MRI Studies of Retinal Neovascularization

描述(申请人提供)：所有哺乳动物视网膜细胞的能量代谢与对钙等离子的需求有关。这种代谢离子需求轴在正常的视网膜功能和健康的视力中起着核心作用。在早产儿视网膜病变(ROP)和糖尿病视网膜病变等疾病中，视力丧失和失明与视网膜新生血管(NV)的出现有关。与视网膜NV相关的病理生理学机制尚不清楚，尽管神经元功能障碍和扰动的离子稳态都被认为是重要的因素。目前尚不清楚在视网膜NV出现之前以及在引起视网膜NV的视网膜区域是否发生了异常的离子需求。这些时间和空间的知识差距目前还不能解决，因为目前的方法要么缺乏空间特异性(例如视网膜电信号)，要么缺乏提供体内离子需求的功能度量(组织学)。我们提出了一种新的非侵入性测量视网膜层特定离子需求的方法，该方法也可以应用于NV的实验啮齿动物模型。这种方法，即锰增强磁共振成像(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这一事实，是一种强大的MRI对比剂。我们已经证实，在系统地给觉醒的啮齿动物注射无毒量的MnCl2后，已知的视网膜层特异性的神经元功能/离子需求在光和暗适应期间的变化可以通过高分辨率的MEMRI来稳健地测量。我们的假设是，视网膜NV的出现将在时间和空间上与神经元功能异常有关，如通过扰动的锰摄取来评估。目的1：验证大鼠和小鼠视网膜NV与血管和无血管视网膜交界处(即视网膜NV的部位)对Mn2+摄取异常的预测。这项创新性研究的结果将有助于阐明异常的离子需求是否在视网膜前NV的发展中起重要作用。这一应用中的新方法也将有助于功能磁共振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的离子需求是否在视网膜前新生血管的发展中发挥重要作用，视网膜前新生血管是早产和糖尿病导致视力丧失和失明的主要原因。这一应用中的新方法也将有助于功能磁共振在视网膜疾病研究中的进步。

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.