Manganese-enhanced MRI Studies of Retinal Neovascularization

视网膜新生血管的锰增强 MRI 研究

• 批准号: 7404426
• 负责人: BRUCE A. BERKOWITZ
• 金额: $ 22.12万
• 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 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7404426
• 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中的能量代谢与对钙等离子的需求有关。该代谢离子需求轴在正常的视网膜功能中起着核心作用，因此具有健康的视力。视力和失明的丧失与诸如预性早产（ROP）和糖尿病性视网膜病变等疾病中的视网膜新血管形成（NV）的出现有关。尽管神经元功能障碍和扰动的离子稳态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。尚不清楚在视网膜NV出现之前和在产生视网膜NV的视网膜区域之前是否发生异常离子需求。目前无法解决这些时间和空间知识差距，因为当前方法缺乏空间特异性（例如电视图）或提供体内离子需求功能指标的能力（组织学）。我们提出了一种新的方法，用于非侵入性测量视网膜层特异性离子需求，也可以应用于NV的实验啮齿动物模型。这种方法是锰增强的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，并且是强大的MRI对比剂。我们已经验证了在光和黑暗适应过程中神经元功能 /离子需求的已知视网膜特异性变化可以通过高分辨率memri在系统性地给出无毒量的MNCL2以清醒啮齿动物后的高分辨率MEMRI来牢固地测量。我们上覆的假设是，通过扰动的锰摄取评估，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在一起。目的1：测试以下预测，即大鼠和小鼠模型中的视网膜NV与血管和血管视网膜边界的MN2+摄取异常（指示了离子需求）（即视网膜NV的部位）有关。这项创新研究的结果将有助于阐明异常离子需求是否在前NV的发展中起重要作用。该应用程序中的新方法还将有助于用于研究视网膜疾病的功能MRI。这项创新研究的结果将有助于阐明异常离子需求是否在产前新的新血管形成发展中起重要作用，这是早产和糖尿病的视力丧失和失明的主要原因。该应用程序中的新方法还将有助于用于研究视网膜疾病的功能MRI。

项目成果

Light-dependent changes in outer retinal water diffusion in rats in vivo.

大鼠体内外视网膜水扩散的光依赖性变化。

• 发表时间: 2012
• 期刊: Molecular vision
• 影响因子: 2.2
• 作者: Bissig,David;Berkowitz,BruceA
• 通讯作者: Berkowitz,BruceA

Quantitative mapping of ion channel regulation by visual cycle activity in rodent photoreceptors in vivo.

• DOI: 10.1167/iovs.08-2958
• 发表时间: 2009-04
• 期刊: Investigative ophthalmology & visual science
• 影响因子: 4.4
• 作者: Berkowitz BA;Roberts R;Oleske DA;Chang M;Schafer S;Bissig D;Gradianu M
• 通讯作者: Gradianu M

Diminished vision in healthy aging is associated with increased retinal L-type voltage gated calcium channel ion influx.

• DOI: 10.1371/journal.pone.0056340
• 发表时间: 2013
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Bissig D;Goebel D;Berkowitz BA
• 通讯作者: Berkowitz BA

Toward clinical application of manganese-enhanced MRI of retinal function.

• DOI: 10.1016/j.brainresbull.2009.06.002
• 发表时间: 2010-02-15
• 期刊: Brain research bulletin
• 影响因子: 3.8
• 作者: Tofts PS;Porchia A;Jin Y;Roberts R;Berkowitz BA
• 通讯作者: Berkowitz BA

Intraretinal calcium channels and retinal morbidity in experimental retinopathy of prematurity.

早产儿实验性视网膜病变的视网膜内钙通道和视网膜发病率。

• 发表时间: 2011
• 期刊: Molecular vision
• 影响因子: 2.2
• 作者: Berkowitz,BruceA;Bissig,David;Bergman,Deborah;Bercea,Emanuela;Kasturi,VijayaK;Roberts,Robin
• 通讯作者: Roberts,Robin