Novel combinatory therapy for experimental ischemic stroke

实验性缺血性中风的新型组合疗法

• 批准号: 10330435
• 负责人: Nicolas G. Bazan
• 金额: $ 32.77万
• 依托单位: LSU HEALTH SCIENCES CENTER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-05-01 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10330435
• 关键词: Acute; Address; Affect; Aftercare; Alteplase; Alzheimer' s Disease; Aspirin; Attenuated; Behavioral; Blood - brain barrier anatomy; Brain; Brain Injuries; Cause of Death; Cell Survival; Cerebral Ischemia; Cerebrovascular Disorders; Clinical Research; Combined Modality Therapy; Data; Dose; Early treatment; Eicosanoids; Ensure; Equilibrium; Event; Goals; Histologic; Homeostasis; Immune response; Inflammation; Inflammatory; Inflammatory Response; Interneurons; Investigational Therapies; Ischemia; Ischemic Penumbra; Ischemic Stroke; Isomerism; Lead; Longevity; Mediating; Microglia; Middle Cerebral Artery Occlusion; Modeling; Molecular Weight; Motor; Motor Cortex; Neurons; Parkinson Disease; Pathology; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacology; Process; Public Health; Rattus; Recovery; Recovery of Function; Reperfusion Injury; Research; Resolution; Signal Pathway; Signal Transduction; Silicon; Site; Stroke; Testing; Therapeutic; Therapeutic Intervention; United States; aged; angiogenesis; antagonist; brain cell; disability; functional outcomes; fundamental research; in vivo; indexing; innovation; lipid mediator; macrophage; nervous system disorder; neural network; neurogenesis; neuroinflammation; neurological recovery; neuronal circuitry; neuronal survival; neuroprotectin D1; neuroprotection; neurovascular unit; novel; novel strategies; platelet activating factor receptor; post stroke; preservation; primary outcome; repaired; response; small molecule; stroke model; stroke survivor; stroke therapy; synergism; targeted treatment; therapeutic development; tool; translational impact

PROJECT SUMMARY / ABSTRACT Stroke is a leading cause of death and permanent disability, with an estimated impact on public health of $73.7 billion per year in the United States. Ischemic stroke accounts for over 85% of stroke cases. Therapeutic options for ischemic stroke are limited. Early treatment with recombinant tissue-plasminogen activator (tPA) only benefits a fraction of patients. In addition, this treatment does not target immuno-inflammatory events during stroke. Ischemia-reperfusion damage is associated with dysregulation of multiple neuroinflammatory signaling pathways that causes irreversible damage to neuronal circuits resulting in the pathologies that affect stroke survivors. Our multi-PI team with extensive, complementary, and unique expertise and access to multiple research tools will use a rat model to investigate the efficacy of a novel approach to pharmacologically resolve neuroinflammatory disruptions triggered by experimental ischemic stroke and thus preserve neuronal network integrity and promote neurologic recovery. Our central hypothesis is that blocking pro- inflammatory platelet activating factor receptor (PAFR) together with administration of docosanoids will lead to sustained neurological recovery and protect neuronal circuits in the primary motor cortex after ischemic stroke. Compelling preliminary data support this hypothesis. We have identified a low molecular weight PAFR antagonist, LAU-0901, which will be administered together with the aspirin-triggered (AT) isomer, AT-NPD1 (aspirin-triggered neuroprotectin D1), our lead docosanoid, in the studies proposed for this application. We predict that our new experimental combination therapy that targets mechanisms of motor circuit damage by blocking pro-inflammatory PAF signaling will reduce damage and enhance survival by ensuring the availability of pro-resolving and neuroprotective lipid mediators following middle cerebral artery occlusion (MCAo). We propose two specific aims: 1) To test the hypothesis that combined blocking of pro- inflammatory PAF plus treatment with docosanoids after MCAo will lead to sustained neurological recovery, and 2) Test the prediction that pro-homeostatic lipid mediator pathways are restored by combination treatment for experimental ischemic stroke. The scientific premise of the proposed research is to identify key network processes in adaptive brain plasticity, which may help to predict functional outcome and may also lead to development of therapeutic interventions to support and promote recovery after stroke. This innovative therapeutic approach may also be applicable to the treatment of other neurological diseases with an inflammatory component such as Alzheimer's disease, Parkinson's disease and others.

项目摘要 /摘要 中风是死亡和永久残疾的主要原因，估计对公共卫生的影响为73.7美元 美国每年十亿美元。缺血性中风占中风病例的85％以上。治疗性 缺血性中风的选项有限。早期用重组组织 - 质激活激活剂（TPA）治疗 只有一小部分患者受益。此外，该治疗方法不针对免疫炎症事件 在中风期间。缺血 - 再灌注损害与多种神经炎症性的失调有关 信号通路会对神经元电路造成不可逆转的损害，导致影响的病理 中风幸存者。我们具有广泛，互补和独特的专业知识和访问权限的Multi-Pi团队 多种研究工具将使用大鼠模型来研究一种新型药理方法的功效 解决由实验性缺血性中风触发的神经炎症破坏，从而保留神经元 网络完整性并促进神经系统恢复。我们的核心假设是阻止 炎症血小板激活因子受体（PAFR）以及二战的给药 将导致持续的神经系统恢复并保护一级运动皮层中的神经元电路 缺血性中风。令人信服的初步数据支持这一假设。我们已经确定了一个低 分子量PAFR拮抗剂LAU-0901，将与阿司匹林触发一起施用 （AT）异构体AT-NPD1（阿司匹林触发的神经保护素D1），我们的铅docosanoid，在提出的研究中 此应用程序。我们预测我们的新实验组合疗法针对运动机制 通过阻止促炎性PAF信号传导的电路损害将减少损害，并通过 确保在脑中动脉中的促促和神经保护性脂质介质的可用性 闭塞（MCAO）。我们提出了两个具体的目的：1）检验以下假设： MCAO后使用docosanoids的炎症性PAF和治疗将导致持续的神经系统恢复， 2）测试以下预测，即通过组合处理恢复启用式脂质介质途径 用于实验性缺血性中风。拟议研究的科学前提是确定关键网络 自适应脑可塑性中的过程，这可能有助于预测功能结果，也可能导致 开发治疗干预措施，以支持和促进中风后康复。这种创新 治疗方法也可能适用于治疗其他神经系统疾病 炎症成分，例如阿尔茨海默氏病，帕金森氏病等。

项目成果

Learning from the Fly Photoreceptor on How Synapses Integrate Gene Expression to Sustain Retina and Brain Function.

从苍蝇感光器中学习突触如何整合基因表达来维持视网膜和大脑功能。

• DOI: 10.1016/j.neuron.2019.02.004
• 发表时间: 2019
• 期刊: Neuron
• 影响因子: 16.2
• 作者: Bazan,NicolasG;Gordon,WilliamC
• 通讯作者: Gordon,WilliamC

Correction to: cRel and Wnt5a/Frizzled 5 Receptor-Mediated Inflammatory Regulation Reveal Novel Neuroprotectin D1 Targets for Neuroprotection.

• DOI: 10.1007/s10571-022-01239-y
• 发表时间: 2023-04
• 期刊: Cellular and molecular neurobiology
• 影响因子: 4