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和健康视力中起着核心作用。在诸如早产儿视网膜病变（ROP）和糖尿病视网膜病变等疾病中，视力丧失和失明与视网膜新生血管（NV）的出现有关。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相关的病理生理机制尚不清楚。目前尚不清楚异常离子需求是否发生在视网膜NV出现之前以及导致视网膜NV的视网膜区域。由于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功能指标的能力（组织学），因此目前无法解决这些时空知识空白。我们提出了一种非侵入性测量视网膜层特异性离子需求的新方法，该方法也可以应用于NV的实验性啮齿动物模型。这种方法，锰增强MRI (MEMRI)，利用锰（Mn2+）离子是钙等各种离子的替代生物标志物，是一种强MRI造影剂。我们已经证实，在清醒的啮齿动物系统给予无毒量的MnCl2后，已知的视网膜层特异性变化在光和暗适应过程中神经元功能/离子需求可以通过高分辨率MEMRI进行可靠测量。我们的假设是，视网膜NV的出现将在时间和空间上与异常的神经元功能联系起来，通过紊乱的锰摄取来评估。目的1：验证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）的Mn2+摄取异常（表明离子需求紊乱）有关的预测。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的发展中起重要作用。该应用的新方法也将有助于推进功能MRI对视网膜疾病的研究。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的发展中起重要作用，而视网膜前新生血管是早产和糖尿病中视力丧失和失明的主要原因。该应用的新方法也将有助于功能性MRI在视网膜疾病研究中的发展。

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.