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Ischemia-induced injury to neuronal processes: role of cofilin-actin rod formation

缺血引起的神经元过程损伤：丝切蛋白-肌动蛋白杆形成的作用

基本信息

批准号：
10664943
负责人：
RAYMOND A SWANSON
金额：
--
依托单位：
VETERANS AFFAIRS MED CTR SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10664943
关键词：
Acceleration Actins Acute Address Affect Animal Model Area Axon Behavior assessment Biochemical Bioenergetics Brain Ischemia Cell Culture Techniques Cells Clinical Dendrites Event Failure Fluorescent Probes Forelimb Genetic Genetic Induction Glucose Histologic Hour Individual Inflammation Inflammatory Injury Intervention Ischemia Ischemic Stroke Knockout Mice Link Location Measures Mediating Methods Modeling Motor Mus NADPH Oxidase Nerve Degeneration Neurites Neurons Outcome Oxidation-Reduction Oxidative Stress Induction Oxygen Preparation Process Reaction Reperfusion Therapy Rod Role Site Specific qualifier value Stimulus Stroke Sulfhydryl Compounds Superoxides Testing Therapeutic Time Transfection Uncertainty Vertebral column Work cofilin depolymerization deprivation dexterity disability functional outcomes glial activation improved intervention effect live cell imaging motor function improvement motor function recovery motor impairment motor recovery neuron loss neuronal survival oxidant stress pharmacologic post stroke preservation real-time images skills stroke model therapeutic target

项目摘要

Disability caused by ischemic stroke results not only from neuronal death, but also from injury to axons and dendrites of surviving neurons. The mechanisms by which ischemia causes injury to these neuronal processes are not well understood, and have not been well-explored as a therapeutic target. Cofilin-actin rods are 1:1 linear aggregates of cofilin-1 and actin that form in neuronal processes under conditions of ATP depletion or oxidant stress. These rods cause degeneration of the neuronal processes in which they persist. Recent studies demonstrate that cofilin-actin rods form in neurons during and after brain ischemia, and that their formation can be suppressed genetically and pharmacologically. Here we will determine the extent to which suppression of rod formation (or accelerated rod dissolution) can promote neurite survival and improve motor function after stroke. We will use transient and permanent models of stroke in the mouse to evaluate effects of rod suppression on survival of neuronal processes at specified intervals after ischemia. We will evaluate the effects of rod suppression on motor impairment and recovery using a skilled reaching task and other measures of forelimb dexterity. We also aim to better elucidate the role of inflammation and subcellular mechanisms that drive rod formation and link rod formation to subsequent neurite degeneration. We will employ subcellular fluorescent probes and real- time imaging in cell culture preparations to determine why rods form and persist in specific locations of neurons, and do so even after the ischemic stimuli are removed; whether the persistence of cofilin-actin rods represent stable aggregates; and whether rod formation influences bioenergetic failure in the affected neurites.

缺血性卒中引起的功能障碍不仅是神经元死亡的结果，也是轴突损伤的结果和存活神经元的树突。缺血引起这些神经元损伤的机制这些过程尚未被很好地理解，并且尚未作为治疗靶点被很好地探索。丝切蛋白-肌动蛋白视杆细胞是在神经元突起中形成的cofilin-1和肌动蛋白的1：1线性聚集体， ATP耗竭或氧化应激。这些杆导致神经元过程的退化，坚持。最近的研究表明，cofilin-actin棒形成于脑过程中和脑后的神经元中，缺血，并且它们的形成可以在遗传学上被抑制和抑制。这里我们将确定抑制视杆形成（或加速视杆溶解）可促进神经突存活和改善中风后的运动功能。我们将使用瞬态和永久模型，在小鼠中风中评估视杆细胞抑制对神经元过程存活的影响，缺血后的时间间隔。我们将评估视杆细胞抑制对运动障碍的影响，恢复使用熟练的达到任务和其他措施的前肢灵活性。我们还致力于更好地阐明炎症的作用和驱动杆形成和连接杆的亚细胞机制神经突变性。我们将使用亚细胞荧光探针和真实的- 细胞培养制备物中的时间成像，以确定为什么杆形成并持续存在于细胞的特定位置，神经元，甚至在缺血刺激被移除后也是如此;是否cofilin-actin的持续存在杆代表稳定的聚集体;以及杆的形成是否会影响生物能量的失败，影响神经突