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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.

缺血性中风导致的残疾不仅是神经元死亡的结果，还与轴突损伤有关和幸存神经元的树突。缺血导致这些神经元损伤的机制过程尚未被充分理解，并且尚未作为治疗靶点得到充分探索。丝切蛋白肌动蛋白杆状细胞是 cofilin-1 和肌动蛋白的 1:1 线性聚集体，在以下条件下在神经元过程中形成： ATP 耗尽或氧化应激。这些视杆细胞会导致其所在的神经元过程退化。坚持。最近的研究表明，丝切蛋白-肌动蛋白棒在大脑中和大脑后的神经元中形成缺血，并且可以通过遗传和药理学抑制它们的形成。在这里我们将确定抑制棒形成（或加速棒溶解）可以促进的程度神经突存活并改善中风后的运动功能。我们将使用瞬态和永久模型小鼠中风，以评估视杆细胞抑制对特定条件下神经元过程存活的影响缺血后的间隔。我们将评估视杆细胞抑制对运动障碍的影响使用熟练的伸展任务和其他前肢灵活性措施进行恢复。我们也致力于更好地阐明炎症和驱动杆形成和连接杆的亚细胞机制的作用形成到随后的神经突变性。我们将采用亚细胞荧光探针和真实的在细胞培养制剂中进行时间成像，以确定杆状细胞形成并持续存在于特定位置的原因神经元，甚至在缺血刺激被移除后仍然如此；丝切蛋白-肌动蛋白是否持续存在棒代表稳定的聚集体；以及杆的形成是否影响生物能衰竭受影响的神经突。