The Neuroprotective Potential of TGF-beta Activated Kinase Inhibition in Acute St

TGF-β 激活激酶抑制对急性 ST 的神经保护潜力

• 批准号: 8772484
• 负责人: Louise D. McCullough
• 金额: $ 19.88万
• 依托单位: UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8772484
• 关键词: Acute; Age; Animal Model; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Behavioral; Biological; Blood Vessels; Bone Marrow; Brain Injuries; Brain Ischemia; Cell Adhesion Molecules; Cells; Chimera organism; Chronic; Clinical Research; Clinical Trials; Data; Disease; Drug effect disorder; Ensure; Event; Family; Future; Genetic Models; Goals; Grant; Hour; Immune response; Infarction; Infiltration; Inflammation; Inflammatory; Injury; Interleukin-1; Ischemic Stroke; Knock-out; Lead; Leukocytes; Ligands; MAP Kinase Kinase Kinase; MAP3K7 gene; Mechanics; Mediating; Mediator of activation protein; Microglia; Modeling; Mus; Myelogenous; Myeloid Cells; Nature; Neuraxis; Neurologic; Neurons; Outcome; Pathway interactions; Patient Selection; Patients; Peripheral; Permeability; Phase; Phosphotransferases; Play; Population; Process; Production; Reperfusion Therapy; Role; Series; Signal Pathway; Signal Transduction; Signaling Molecule; Stimulus; Stroke; Systemic disease; Testing; Therapeutic; Therapeutic Intervention; Time; Toll-like receptors; Transforming Growth Factor beta; Transforming Growth Factors; Translating; Tumor Necrosis Factor-alpha; Vasodilation; Work; aged; clinically relevant; cytokine; disability; drug discovery; effective therapy; expectation; functional restoration; improved; inhibitor/antagonist; knockout animal; male; member; monocyte; neuroprotection; neutrophil; novel; post stroke; pre-clinical; pre-clinical therapy; public health relevance; research study; response; sex; small molecule; stroke therapy; theories

DESCRIPTION (provided by applicant): Ischemic stroke is now the most frequent cause of persistent neurologic disability in the US. Despite considerable effort there are no therapies that can reduce injury or restore function once a stroke occurs. Over the past several years, our view of stroke as a "neuronal disease" has been transformed into the concept of stroke as a "neurovascular" disease, and more recently into the novel theory that stroke is truly a "systemic" disease in which peripheral inflammatory processes play a fundamental role. This peripheral immune response is a target for stroke therapy, as reducing peripheral infiltration of circulating leukocytes, specifically monocytes and neutrophils, decreases ischemic injury. Transforming growth factor ¿ activated kinase-1 (TAK1), a member of the mitogen-activated protein kinase kinase kinase (MAP3K) family has been recently recognized as an indispensible signaling molecule in the innate immune response to brain injury. The proposed work will examine the effects of loss of TAK signaling on post-stroke inflammation using selective deletion of TAK in myeloid cells. Mechanistic studies will be performed in TAK1 knockout animals (Aim 1). We will then determine the neuroprotective efficacy of pharmacologically inhibiting TAK in aged mice, a clinically relevant animal model for stroke (Aim 2). These exploratory studies will hopefully identify new biological targets for therapeutic intervention for patients with stroke.

描述（由申请人提供）：目前，缺血性中风是美国持续性神经功能障碍的最常见原因，尽管付出了巨大的努力，但尚无治疗方法。 可以在中风发生后减轻损伤或恢复功能 在过去的几年中，我们将中风视为“神经元疾病”的观点已转变为“神经血管”疾病的概念，最近又转变为新的理论：中风确实是一种“全身性”疾病，其中外周炎症过程发挥着重要作用，这种外周免疫反应是中风治疗的目标，因为减少循环白细胞（特别是单核细胞和中性粒细胞）的外周浸润，可以减少缺血性损伤。转化生长因子 ¿激活激酶-1 (TAK1) 是丝裂原激活蛋白激酶激酶 (MAP3K) 家族的成员，最近被认为是对脑损伤的先天免疫反应中不可或缺的信号分子。拟议的工作将研究损失的影响。使用骨髓细胞中 TAK 的选择性缺失来研究 TAK 信号传导对中风后炎症的影响 将在 TAK1 敲除动物中进行机制研究（目标 1）。在老年小鼠中药理学抑制 TAK，这是一种临床相关的中风动物模型（目标 2）。这些探索性研究有望确定中风患者治疗干预的新生物学靶点。