Manganese-enhanced MRI Studies of Retinal Neovascularization

描述（由申请人提供）：所有哺乳动物视网膜细胞中的能量代谢与对离子如钙的需求有关。这个代谢离子需求轴在正常视网膜功能和健康视力中起着核心作用。视力丧失和失明与诸如早产儿视网膜病变（ROP）和糖尿病视网膜病变等疾病中视网膜新生血管（NV）的出现相关。虽然神经元功能障碍和离子稳态紊乱都被认为是重要的因素，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发生在视网膜NV出现之前以及引起视网膜NV的视网膜区域中。这些时间和空间知识差距目前无法解决，因为目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的功能度量的能力（组织学）。我们提出了一种新的方法来非侵入性地测量视网膜层特定的离子需求，也可以应用于NV的实验啮齿动物模型。这种方法，锰增强MRI（MEMRI），利用锰（Mn 2+）离子是包括钙在内的各种离子的替代生物标志物，并且是一种强MRI造影剂的事实。我们已经验证了已知的视网膜层的神经元功能/离子需求的变化，在光明和黑暗的适应过程中，可以鲁棒地测量高分辨率MEMRI后，系统管理的无毒量的氯化锰清醒啮齿动物。我们的假设是，视网膜NV的外观将在时间和空间上与异常的神经元功能，评估扰动锰摄取。目标1：为了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处的异常Mn 2+摄取（指示受干扰的离子需求）相关的预测（即，视网膜NV的部位）。这项创新研究的结果将有助于澄清是否异常离子需求在视网膜前NV的发展中起着重要作用。该应用中的新方法也将有助于功能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澄清异常离子需求是否在视网膜前新生血管的发展中起重要作用，这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功能MRI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.