Regulation of Capillary Blood Flow in the Retina in Health and in Diabetic Retinopathy

健康和糖尿病视网膜病变中视网膜毛细血管血流的调节

• 批准号: 9233121
• 负责人: ERIC A NEWMAN
• 金额: $ 37.57万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-03-01 至 2021-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9233121
• 关键词: Accounting; Acids; Affect; Amacrine Cells; Arachidonic Acids; Basic Science; Blood capillaries; Blood flow; Brain; Brain imaging; Calcium Signaling; Caliber; Contractile Proteins; Diabetes Mellitus; Diabetic Retinopathy; Diagnosis; Dinoprostone; Epoprostenol; Erythrocytes; Functional Imaging; Functional Magnetic Resonance Imaging; Glucose; Goals; Health; Hyperemia; Image; Immunohistochemistry; Injectable; Injection of therapeutic agent; Insulin-Dependent Diabetes Mellitus; Light; Measures; Mediating; Modeling; Molecular; Monitor; Muller' s cell; Neuroglia; Neurons; Nitric Oxide; Nutrient; Oxygen; Pathology; Pericytes; Presynaptic Terminals; Production; Property; Prostaglandins I; Rattus; Regulation; Retina; Retinal; Signal Transduction; Smooth Muscle Actin Staining Method; Streptozocin; Synapses; Testing; Time; Transgenic Mice; Vasodilator Agents; Vitreous humor; Work; aminoguanidine; arteriole; caldesmon; capillary; clinical Diagnosis; density; diabetic; experimental study; ganglion cell; hemodynamics; in vivo; inhibitor/antagonist; intravitreal injection; neuron loss; neurotransmitter release; ophthalmic artery; pressure; public health relevance; response; retinal neuron; therapy development; tool; vasoactive agent

 DESCRIPTION (provided by applicant): Proper regulation of blood flow is essential for the health and function of the retina. Flicker stimulation evokes increases in blood flow in the retina a response termed functional hyperemia. This response brings additional oxygen and glucose to active neurons. We have recently demonstrated that blood flow is differentially regulated within the three capillary layers in the retina. Flickering light evokes far greater increases in capillar diameter and blood flow in the intermediate capillary layer than in the deep and superficial layers. The goal of this project is to determine the mechanisms responsible for this differential control of blood flow and to establish whether this control is altered in diabetic retinopathy, where functional hyperemia is known to be disrupted. The aims of the project are: Aim 1. Test the hypothesis that selective dilation of intermediate layer capillaries is driven by the activity f nearby neurons. The large flicker-evoked responses of intermediate layer capillaries may arise because synaptic activity near these capillaries is greater than activity near the other capillary layers, leading to greater release of vasodilating agents. This hypothesis will be tested by using local Ca2+ signals within Müller glial cells as an indicator of nearby synaptic activity. Calcium signals will be imaged in different retinal layers using transgenic mice expressing the genetically encoded Ca2+ indicator GCaMP3 in Müller cells. Aim 2. Test the hypothesis that flicker-evoked dilations of capillaries is mediated by production of arachidonic acid metabolites. Flicker-evoked capillary dilations will be monitored in the rat in vivo in the three capillary layers as the signaing of candidate vasodilators is blocked by intravitreal injection of synthesis inhibitors. Candidate vasodilators will also be injected into the vitreous humor and the resulting changes in capillary diameter in the three capillary layers will be monitored. Aim 3. Test the hypothesis that dilation of intermediate layer capillaries is compromised in diabetic retinopathy. Capillary diameter in the three capillary layers will be measured at 0.5, 1, 3 and 6 months after diabetes induction by streptozotocin injection. The effect of aminoguanidine, which reverses the loss of arteriole dilation in the diabetic retina, on capillary dilation will be investigated.

 描述(由申请人提供)：适当调节血液流动对视网膜的健康和功能至关重要。闪烁刺激引起视网膜血流量增加，这种反应被称为功能性充血。这种反应为活跃的神经元带来额外的氧气和葡萄糖。我们最近证明，视网膜中的三个毛细血管层内的血液流动是不同的调节。闪烁的光线在中间毛细血管层引起的毛细血管直径和血流量的增加比深层和浅层大得多。该项目的目标是确定导致这种血流不同控制的机制，并确定这种控制在糖尿病视网膜病变中是否发生改变，在糖尿病视网膜病变中，已知功能性充血被破坏。该项目的目标是：目标1.检验中间层毛细血管选择性扩张是由邻近神经元的活动驱动的假设。中间层毛细血管的大闪烁反应可能是因为这些毛细血管附近的突触活动比其他毛细血管层附近的活动更大，导致血管扩张剂的释放更多。这一假说将通过使用穆勒神经胶质细胞内的局部钙信号作为附近突触活动的指示器来验证。钙信号将在不同的视网膜层使用转基因小鼠进行成像，转基因小鼠在基因上表达 编码钙离子指示剂GCaMP3的Müler细胞。目的2.验证闪烁诱发的毛细血管扩张是由花生四烯酸代谢产物介导的假说。闪烁引起的毛细血管扩张将在大鼠体内的三个毛细血管层中监测，因为玻璃体内注射合成抑制剂阻止了候选血管扩张剂的信号。候选血管扩张剂也将被注射到玻璃体体液中，并将监测由此导致的三层毛细血管直径的变化。目的3.验证糖尿病视网膜病变中间层毛细血管扩张受损的假说。毛细管径 在注射链脲佐菌素诱导糖尿病后0.5个月、1个月、3个月和6个月分别测量3个毛细血管层。氨基胍逆转糖尿病视网膜微动脉扩张的丧失，对毛细血管扩张的影响将被研究。