Cofilin Signaling in Hemorrhagic Stroke

出血性中风中的 Cofilin 信号转导

• 批准号: 10598544
• 负责人: Zahoor Ahmad Shah
• 金额: $ 40.1万
• 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/10598544
• 关键词: Actin-Binding Protein; Actins; Address; Alzheimer' s Disease; American; Animals; Area; Autologous; Autopsy; Behavioral; Binding; Biological Assay; Blood brain barrier dysfunction; Brain; Brain Injuries; Brain hemorrhage; Case Study; Cause of Death; Cell Death; Cells; Central Nervous System; Cerebral hemisphere hemorrhage; Corpus striatum structure; Crossbreeding; Cytoskeletal Proteins; Disease; Enterobacteria phage P1 Cre recombinase; F-Actin; Female; Filament; Functional disorder; Hematoma; Hemin; Human; Immune; Immunofluorescence Immunologic; Impaired cognition; In Vitro; Inflammation; Injections; Injury; Ischemic Stroke; Knock-out; Knockout Mice; Left; Lipopolysaccharides; Maps; Mediating; Mediator; Microfilaments; Microglia; Modality; Modeling; Morbidity - disease rate; Motor; Mus; 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; Recovery; 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; calmodulin-dependent protein kinase II; cofilin; cofilin 2; disability; drug development; drug discovery; effective therapy; experimental study; functional disability; glial activation; improved; inhibitor; 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 cognitive outcome; 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.

出血性卒中仅占总卒中类型的10-15%，但死亡率较高 中风后认知障碍（PSCI）的发病率和幸存者。除了 对于外科手术，脑出血（ICH）没有有效的治疗方法。为了 为了开发有效的治疗方式，必须更好地了解这些途径 在脑出血后，特别是在涉及小胶质细胞活化介导的继发性损伤期间， 神经炎症和PSCI。小胶质细胞在脑损伤中起重要作用， 全面了解小胶质细胞特异性信号在损伤事件中的作用是关键， 减轻ICH引起的损害。三种cofilin亚型：肌动蛋白结合蛋白，cofilin 1（cofilin） 和cofilin 2是F-actin周转和重组的重要调节因子， 这些过程可能导致神经退行性疾病。在病理过程中形成的Cofilin杆/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发挥着至关重要的作用。作为 概念的机制证明，在小鼠中用siRNA或抑制剂靶向cofilin导致降低的 血肿体积，改善神经行为功能和实验性ICH后PSCI。 对人类尸检ICH脑标本的免疫荧光分析也显示了广泛的cofilin 血肿周围区域的小胶质细胞活化。新的发现支持了这样一个科学前提， cofilin信号传导在涉及小胶质细胞活化的ICH的第二阶段中起关键作用， 炎症和随后PSCI，并使我们假设抑制cofilin提供了一种新的 治疗策略提出的假设将在三个目标。Aim 1将鉴定cofilin 在人ICH尸检脑标本中， 免疫荧光将确定丝切蛋白棒/聚集体和PSCI的时空模式 野生型（WT）小鼠在ICH后60天的延长期内。目标2将确定是否 小胶质细胞或神经元cofilin通过使用神经元和 小胶质细胞特异性cofilin敲除小鼠。目的3将研究一种新的治疗潜力， 类，cofilin抑制剂在经历ICH的老龄WT小鼠中的作用。本提案中概述的研究将 提供关于cofilin信号传导在ICH诱导的小胶质细胞活化、炎症和 PSCI和药物发现和开发的潜在治疗剂的鉴定。