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.

由缺血性中风引起的残疾不仅是由神经元死亡而导致的和幸存神经元的树突。缺血对这些神经元造成伤害的机制过程尚未得到充分理解，也没有被充分探索为治疗靶点。 cofilin-actin 杆是Cofilin-1和肌动蛋白的1：1线性骨料，在神经元过程中形成 ATP耗竭或氧化应激。这些棒会导致神经元过程的变性坚持。最近的研究表明，在大脑期间和之后的神经元中形成了Cofilin-actin杆缺血，并且它们的形成可以在遗传和药理上受到抑制。我们会在这里确定杆形成的抑制程度（或加速杆溶解）可以促进神经突生存并改善中风后运动功能。我们将使用瞬态和永久模型的小鼠中的中风以评估杆抑制对指定的神经元过程存活的影响缺血后的间隔。我们将评估杆抑制对运动障碍的影响和使用熟练的达到任务和其他前肢敏捷度措施恢复。我们也打算更好阐明驱动杆形成和连接杆的炎症和亚细胞机制的作用形成了随后的神经突变性。我们将采用亚细胞荧光探针和实现细胞培养准备中的时间成像，以确定为什么在特定位置形成杆并持续神经元，即使去除缺血性刺激后，也要这样做。 cofilin-actin的持久性是否杆代表稳定的聚集体；以及杆形成是否影响生物能衰竭受影响的神经突。