Cofilin Signaling in Hemorrhagic Stroke

出血性中风中的 Cofilin 信号转导

• 批准号: 10380692
• 负责人: Zahoor Ahmad Shah
• 金额: $ 38.63万
• 依托单位: UNIVERSITY OF TOLEDO HEALTH SCI CAMPUS
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-15 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10380692
• 关键词: Actin-Binding Protein; Actins; Address; Alzheimer' s Disease; American; Animals; Area; Autologous; Autopsy; Behavioral; Binding; Biological Assay; Blood - brain barrier anatomy; Brain; Brain Injuries; Brain hemorrhage; Case Study; Cause of Death; Cell Death; Cells; Cerebral hemisphere hemorrhage; Corpus striatum structure; Cytoskeletal Proteins; Disease; Enterobacteria phage P1 Cre recombinase; F-Actin; Female; Functional disorder; Hematoma; Hemin; Human; Immune; Immunofluorescence Immunologic; Impaired cognition; In Vitro; Inflammation; Injections; Injury; Ischemic Stroke; Knock-out; Knockout Mice; Lead; Left; Lipopolysaccharides; Maps; Mediating; Mediator of activation protein; Microfilaments; Microglia; Modality; Modeling; Morbidity - disease rate; Motor; Mus; Neuraxis; Neurites; Neurodegenerative Disorders; Neuronal Injury; Neurons; Operative Surgical Procedures; Outcome; PTGS2 gene; Pathologic; Pathway interactions; Pattern; Phase; Pilot Projects; Play; Prevalence; Process; Protein Isoforms; Publishing; Risk; Rod; Role; Sex Differences; Signal Transduction; Site; Small Interfering RNA; Specimen; Stress; Stroke; Survivors; Synapses; TNF gene; Tail; Testing; Therapeutic; Therapeutic Agents; Therapeutic Studies; Time; Veins; Whole Blood; Wild Type Mouse; actin depolymerizing factor; aged; analog; base; calmodulin-dependent protein kinase II; cofilin; cofilin 2; disability; drug development; drug discovery; effective therapy; experimental study; functional disability; improved; inhibitor; injury recovery; insight; male; migration; mortality; mouse model; neurobehavioral; neuroinflammation; neuron loss; new therapeutic target; novel; novel therapeutic intervention; post stroke cognitive impairment; promoter; public health relevance; spatiotemporal; stroke survivor; stroke therapy; targeted treatment; translational potential

Hemorrhagic stroke constitutes only 10-15% of total stroke types but is responsible for higher mortality rates and survivors suffer from severe disabilities and post-stroke cognitive impairments (PSCI). Except for surgical intervention, there is no effective treatment for intracerebral hemorrhage (ICH). In order to develop effective treatment modalities, it is imperative to gain a better understanding of the pathways that are active after ICH, in particular, during secondary injury involving microglial activation mediated neuroinflammation and PSCI. Microglia play an important role responding to injuries in the brain and a comprehensive understanding of the microglia-specific signaling during episodes of injury are pivotal for mitigating the damage induced by ICH. The three cofilin isoforms: actin binding protein, cofilin1 (cofilin) and cofilin2 are important regulators of F-actin turnover and reorganization and alterations in these processes can lead to neurodegenerative diseases. Cofilin rods/aggregates formed during pathological conditions play a crucial role in microglial activation, synaptic dysfunction and neuronal death. As a mechanistic proof of concept, targeting cofilin with siRNA or inhibitor in mice led to decreased hematoma volume, improved neurobehavioral functions and PSCI after experimental ICH. Immunofluorescence analysis of human autopsy ICH brain specimens also showed widespread cofilin activation in microglia in the perihematoma area. The novel findings support the scientific premise that cofilin signaling plays a key role in the secondary phase of ICH involving microglial activation and inflammation and subsequent PSCI and led us to hypothesize that inhibition of cofilin presents a novel therapeutic strategy. The proposed hypothesis will be addressed in three aims. Aim 1 will identify cofilin rods/aggregates and microglial activation in human ICH autopsy brain specimens by performing immunofluorescence. The spatiotemporal pattern of cofilin rods/aggregates and PSCI will be determined in wildtype (WT) mice over a protracted period of 60 days following ICH. Aim 2 will identify whether microglial or neuronal cofilin is mediating neuroinflammation and PSCI after ICH by using neuron and microglia-specific cofilin knockout mice. Aim 3 will study the therapeutic potential of a novel first of its class, cofilin inhibitor in aged WT mice subjected to ICH. The studies outlined in this proposal will provide insights on the role of cofilin signaling in ICH induced-microglial activation, inflammation and PSCI and the identification of potential therapeutic agents for drug discovery and development.

出血性中风仅占总中风类型的10-15％，但负责较高的死亡率 比率和幸存者患有严重的残疾和中风后认知障碍（PSCI）。除了 对于手术干预，没有有效的脑出血（ICH）治疗。为了 开发有效的治疗方式，必须更好地了解途径 涉及小胶质激活介导的继发性损伤期间，尤其是在ICH之后活跃的 神经炎症和PSCI。小胶质细胞对大脑的伤害做出反应和 在伤害发作期间对小胶质细胞特异性信号传导的全面了解至关重要 减轻ICH诱导的损害。三种cofilin同工型：肌动蛋白结合蛋白，cofilin1（cofilin） 和cofilin2是F-肌动新转盘和重组和改变的重要调节因子 过程可以导致神经退行性疾病。病理期间形成的cofilin棒/聚集体 条件在小胶质激活，突触功能障碍和神经元死亡中起着至关重要的作用。作为 概念的机理证明，针对小鼠的siRNA或抑制剂靶向cofilin导致下降 实验性ICH后，血肿体积，改善神经行为功能和PSCI。 人尸检ICH脑样本的免疫荧光分析也显示出广泛的Cofilin 小胶质细胞的激活。小说的发现支持科学前提 cofilin信号传导在涉及小胶质激活和 炎症和随后的PSCI，使我们假设抑制cofilin呈现出一种新颖 治疗策略。提出的假设将以三个目的解决。 AIM 1将识别Cofilin 人ICH尸检大脑标本中的杆/聚集体和小胶质细胞激活通过执行 免疫荧光。 Cofilin杆/聚集体和PSCI的时空图案将被确定 在ICH后60天的长时间期间，在WildType（WT）的小鼠中。 AIM 2将确定是否 通过使用神经元和 小胶质细胞特异性Cofilin敲除小鼠。 AIM 3将研究其小说的治疗潜力 经过ICH的老年WT小鼠中的Cofilin抑制剂。该提议中概述的研究将 提供有关Cofilin信号传导在ICH引起的微乳化激活，炎症和 PSCI以及对药物发现和发育的潜在治疗剂的鉴定。