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，钙等离子的稳态被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和视力下降之间的关系尚未在体内进行测试。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显示体内二价阳离子流入逐渐增加，这导致临床上可检测到的视力下降和组织学变化。在第一个目标中，我们将建立视觉表现、离子调节和组织学之间的基线关系。将使用创新的功能性 MRI 方法评估离子调节；锰增强 MRI (MEMRI)，用于无创测量成年大鼠大脑和视网膜对锰离子 (Mn2+) 的吸收。 Mn2+离子是一种强MRI造影剂，通过L型电压门控钙通道进入神经元。全身注射无毒量的 MnCl2 后，其在神经元组织中积累的程度是离子调节的指标。在第二个目标中，神经元阳离子流入将通过长期服用尼莫地平（一种可渗透血脑/视网膜屏障的钙通道阻滞剂）来改变。具体目标 1：检验视网膜和大脑中较高水平的锰摄取与视觉系统中与年龄相关的渐进性变化相关的假设。我们将每隔三个月对 3 至 [24] 个月龄的大鼠进行行为测量视觉功能。每轮测试后，我们将暂时遮盖一只眼睛，并使用 MEMRI 测量视网膜和大脑对视觉刺激（未遮盖眼睛）和黑暗（遮盖眼睛）的 Mn2+ 摄取。 Mn2+ 摄取与年龄相关的增加将支持神经元 Ca2+ 流入与年龄相关增加的离体发现。我们将与年龄相关的视觉功能变化与纵向 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。具体目标 2：检验长期服用二氢吡啶 L 型钙通道阻滞剂可改善与年龄相关的视觉系统衰退的假设。我们将目标 1 中描述的视觉功能纵向变化模式与长期服用尼莫地平的大鼠和相关对照中测量的视觉功能纵向变化模式进行比较。在最后一次视力测试之后，我们将比较每组的组织学数据。尼莫地平治疗组视觉功能的保留支持了先前关于二氢吡啶 L 型钙通道阻滞剂的神经保护作用的发现。这些实验将阐明神经元离子调节的年龄相关变化与视觉功能的行为明显变化之间的假设联系。积极的发现将提供强有力的证据，证明与年龄相关的视力下降与 L 型电压门控 Ca2+ 通道进行性离子失调有关，并且这些下降可以通过药物干预得到改善。