Cofilin Signaling in Hemorrhagic Stroke

出血性中风中的 Cofilin 信号转导

• 批准号: 10191059
• 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/10191059
• 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/antagonist; 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

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%，但导致较高的死亡率 存活率和幸存者患有严重残疾和中风后认知障碍(PSCI)。除 对于脑出血(ICH)，目前尚无有效的外科治疗方法。为了 发展有效的治疗模式，必须更好地了解这些途径 在脑出血后，尤其是在涉及小胶质细胞激活的继发性损伤过程中，它们是活跃的 神经炎症和PSCI。小胶质细胞在脑损伤的反应中起着重要作用 全面了解小胶质细胞在损伤过程中的信号转导对于 减轻脑出血造成的损害。Cofilin的三种亚型：肌动蛋白结合蛋白、cofilin 1(Cofilin) 和cofilin 2是F-肌动蛋白翻转、重组和改变的重要调节因子 这些过程可能会导致神经退行性疾病。在病理过程中形成的Cofilin棒/聚集体 条件在小胶质细胞激活、突触功能障碍和神经元死亡中起着至关重要的作用。作为一名 机制验证概念，靶向cofilin与siRNA或抑制剂在小鼠体内导致减少 实验性脑出血后血肿量、神经行为功能和PSCI的改善。 人类尸检脑出血标本的免疫荧光分析也显示广泛的粘连蛋白 血肿周围小胶质细胞活化。新的发现支持这样一个科学前提 Cofilin信号在脑出血的第二阶段发挥关键作用，涉及小胶质细胞的激活和 炎症和随后的PSCI，并导致我们假设抑制Cofilin呈现一种新的 治疗策略。提出的假设将在三个目标中加以阐述。目标1将确定Cofilin 人脑出血尸检标本中视杆/聚集体和小胶质细胞的激活 免疫荧光。将确定Cofilin棒/聚集体和PSCI的时空模式 野生型(WT)小鼠在脑出血后60天的延长时间内。目标2将确定是否 小胶质细胞或神经元粘连蛋白通过利用神经元和神经细胞介导脑出血后神经炎症和PSCI 小胶质细胞特异性cofilin基因敲除小鼠。目标3将研究其第一个新的治疗潜力 类，Cofilin抑制剂在老年WT小鼠脑出血中的作用。这项提案中概述的研究将 提供有关cofilin信号在脑出血诱导的小胶质细胞活化、炎症和 PSCI和为药物发现和开发确定潜在的治疗药物。