Manganese-Enhanced MRI Studies of Vision Loss with Aging

随年龄增长而丧失视力的锰增强 MRI 研究

• 批准号: 8313932
• 负责人: David Philip Bissig
• 金额: $ 4.72万
• 依托单位: WAYNE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-06 至 2014-03-05
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8313932
• 关键词: Activities of Daily Living; Adult; Age; Age-Months; Aging; Animals; Biological Markers; Biological Preservation; Blindness; Blood; Blood - brain barrier anatomy; Brain; Calcium; Calcium Channel; Calcium Channel Blockers; Cations; Chronic; Contrast Media; Contrast Sensitivity; Darkness; Data; Dihydropyridines; Divalent Cations; Eye; Goals; Histology; Homeostasis; Impairment; Injection of therapeutic agent; Intervention; Ions; L-Type Calcium Channels; Link; Magnetic Resonance Imaging; Manganese; Measures; Memory; Methods; Metric; Neuronal Dysfunction; Neurons; Nimodipine; Pattern; Photic Stimulation; Physiology; Rattus; Regulation; Research; Retina; Retinal; Rodent; Structure; Testing; Tissues; Vision; Vision Tests; Visual; Visual Acuity; Visual system structure; age related; aged; analog; computer generated; depressive symptoms; dihydropyridine; healthy aging; improved; in vivo; innovation; manganese chloride; research study; response; senescence; social; uptake; visual performance; voltage

DESCRIPTION (provided by applicant): The overall goal of our research is to improve treatment of age-related vision loss. In neurons obtained from aged animals, disrupted homeostasis of ions such as calcium causes subsequent neuronal dysfunction which may contribute to visual senescence. However, the relationship between age-related ion dysregulation and visual decline remains untested in vivo. Our overarching hypothesis is that with increasing age the retina and central visual structures demonstrate progressively increased divalent cation influx in vivo, which contributes to clinically detectable declines in vision and changes in histology. In the first Aim, we will establish a baseline relationship between visual performance, ion regulation, and histology. Ion regulation will be assessed using an innovative functional MRI method; manganese enhanced MRI (MEMRI), to non-invasively measure brain and retinal uptake of manganese ion (Mn2+) in adult rats. Mn2+ ion is a strong MRI contrast agent and enters neurons through L-type voltage-gated calcium channels. The extent of its accumulation in neuronal tissue following systemic injection of a non-toxic amount of MnCl2 is a metric of ion regulation. In the second Aim, neuronal cation influx will be modified through chronic administration of nimodipine, a blood-brain/retina barrier-permeable calcium channel blocker. Specific Aim 1: To test the hypothesis that higher levels of manganese uptake in retina and brain correlate with progressive age-related changes in the visual system. We will behaviorally measure rats' visual function in three-month intervals, from 3 to [24] months of age. After each round of testing, we will temporarily patch one eye and measure retinal and brain Mn2+ uptake in response to visual stimulation (unpatched eye) and darkness (patched eye) with MEMRI. Age-related increases in Mn2+ uptake would support ex vivo findings of age-related increases in neuronal Ca2+ influx. We will compare age-related changes in visual function with longitudinal MEMRI data and endpoint histological data from the retina and central visual structures. Specific Aim 2: To test the hypothesis that chronic administration of a dihydropyridine L-type calcium channel blocker ameliorates age-related declines in the visual system. We will compare the pattern of longitudinal changes in visual function described in Aim 1 with that measured in rats chronically administered nimodipine and in relevant controls. Following the last vision testing session, we will compare histological data from each group. Preservation of visual function in the nimodipine-treated group would support previous findings of neuroprotective effects of dihydropyridine L-type calcium channel blockers. These experiments will clarify the hypothesized link between age-related changes in neuronal ion regulation and behaviorally-evident changes in visual function. Positive findings would provide strong evidence that age-related vision declines are linked to progressive ion dysregulation via L-type voltage gated Ca2+ channels, and that these declines can be ameliorated through pharmacologic intervention.

描述（由申请人提供）：我们研究的总体目标是改善与年龄相关的视力丧失的治疗。在从老年动物获得的神经元中，钙等离子的稳态破坏会导致随后的神经元功能障碍，这可能导致视觉衰老。然而，与年龄相关的离子失调与视觉下降之间的关系在体内仍未测试。我们的总体假设是，随着年龄的增长，视网膜和中央视觉结构在体内逐渐增加了二价阳离子的涌入，这有助于临床可检测到的视力下降和组织学变化。在第一个目标中，我们将建立视觉性能，离子调节和组织学之间的基线关系。离子调节将使用创新的功能MRI方法进行评估；锰增强的MRI（MEMRI），以非侵入性测量成年大鼠的锰离子（MN2+）的视网膜摄取。 MN2+离子是强大的MRI对比剂，并通过L型电压门控钙通道进入神经元。全身注射无毒的MNCL2后，其在神经元组织中积累的程度是离子调节的度量。在第二个目标中，神经元阳离子的涌入将通过长期给药尼莫地平（一种血脑/视网膜屏障 - 可渗透的钙通道阻滞剂）来改变。特定目的1：检验以下假设：视网膜中较高水平的锰吸收水平与视觉系统中与年龄相关的渐进性变化相关。我们将以三个月的时间间隔（从3个月大到24个月大）在行为上测量大鼠的视觉功能。每一轮测试后，我们将暂时修补一只眼睛，并用MEMRI响应视觉刺激（未捕获的眼睛）和黑暗（贴斑的眼睛）来测量视网膜和脑MN2+摄取。 MN2+摄取年龄相关的增加将支持在神经元Ca2+涌入中与年龄相关的增加的发现。我们将将视觉功能与年龄相关的变化与纵向MEMRI数据以及来自视网膜和中央视觉结构的终点组织学数据进行比较。具体目的2：为了检验以下假设：二氢吡啶L型钙通道阻滞剂的长期给药可改善与年龄相关的视觉系统下降。我们将比较AIM 1中描述的视觉功能纵向变化的模式与在长期施用的Nimodipine和相关控制中测得的纵向变化。在上次视觉测试会话之后，我们将比较每个组的组织学数据。维持二胺处理的组中视觉功能的保存将支持二氢吡啶L型钙通道阻滞剂的神经保护作用的先前发现。这些实验将阐明神经离子调节与年龄相关的变化与视觉功能的行为更改之间的假设联系。积极的发现将提供有力的证据表明，与年龄相关的视力下降与通过L型电压门控Ca2+通道与进行性离子失调有关，并且可以通过药理干预来改善这些下降。