Role of Neuronal p38 MAPK after Repetitive Mild TBI

重复性轻度 TBI 后神经元 p38 MAPK 的作用

• 批准号: 10266820
• 负责人: Erin McGuire Buckley
• 金额: $ 44.5万
• 依托单位: GEORGIA INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-30 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10266820
• 关键词: Acute; Affect; Attenuated; Automobile Driving; Biological Markers; Biomechanics; Blood Vessels; Blood flow; Brain; Cerebrovascular Circulation; Chronic; Clinical Research; Closed head injuries; Cognition; Cognitive; Cognitive deficits; Core-Binding Factor; Coupled; Data; Dementia; Disease; Functional disorder; Genetic; Goals; Hippocampus (Brain); ITGAX gene; Immune signaling; Immunohistochemistry; Impaired cognition; Inflammatory; Injections; Injury; Interleukin-17; Knock-out; Knockout Mice; Knowledge; Lead; Link; Long-Term Effects; MAP Kinase Gene; Measurement; Measures; Mediating; Microglia; Modeling; Molecular; Mus; Nerve Degeneration; Neurobehavioral Manifestations; Neurologic; Neurologic Dysfunctions; Neurologic Symptoms; Neuronal Dysfunction; Neurons; Nitric Oxide; Optics; Outcome; PTPRC gene; Pathway interactions; Patients; Phagocytes; Pharmaceutical Preparations; Pharmacology; Phenotype; Phosphorylation; Physiological; Pre-Clinical Model; Production; Regulation; Research; Role; Severities; Signal Transduction; Stress; Synapsins; Systems Analysis; Tail Suspension; Tamoxifen; Techniques; Testing; Tissues; Transgenic Mice; Traumatic Brain Injury; Tumor-infiltrating immune cells; Wild Type Mouse; Wood material; Work; adverse outcome; attenuation; base; biological adaptation to stress; cell type; cerebrovascular; cognitive change; cognitive function; cytokine; design; emotional symptom; improved; inflammatory marker; inhibitor/antagonist; insight; intraperitoneal; knock-down; mild traumatic brain injury; morris water maze; mouse model; neuroinflammation; outcome prediction; overexpression; p38 Mitogen Activated Protein Kinase; physical symptom; preclinical study; promoter; psychological symptom; relating to nervous system; response; response to injury; success; therapeutically effective; transcriptome sequencing; transcriptomics; vector

PROJECT SUMMARY Mild traumatic brain injuries (mTBIs) affect millions per year, leaving 10-40% of patients with long-lasting (>1 month) physical, emotional, psychological, and cognitive symptoms for which effective therapeutic strategies are lacking. Moreover, repetitive mTBI (rmTBI) can lead to cumulative severity and duration of adverse consequences. Clinical and preclinical studies have shown that the spectrum of neurological sequelae seen post-injury cannot be explained by biomechanical impact forces alone. Injury mechanisms underlying neurological symptoms after repetitive mild traumatic brain injury (rmTBI) are poorly understood and may be distinct from more severe forms of TBI. Working together, Drs. Wood and Buckley (co-PIs) have recently discovered that neuronal p38 MAPK phosphorylation is acutely up-regulated in mice predicted to have worse cognitive outcomes after rmTBI. p38 MAPK is a stress-response pathway with a well-established pro- inflammatory role in microglia after TBI. However, there is a gap in knowledge on the role of neuronal p38 MAPK phosphorylation in regulating response to injury that leads to cellular and cognitive dysfunction after TBI. Our overall hypothesis is that p38 MAPK phosphorylation, especially within neurons, drives both 1) acute changes in cytokine expression, microglia activation, and cerebral blood flow and 2) chronic changes in microglia and cognitive deficits after rmTBI. Given limited knowledge on the role of neuronal phospho-signaling in driving these neuroinflammatory, cognitive, and physiologic changes after TBI, the goal of this proposal is to expand our knowledge on the role of p38 MAPK phosphorylation on brain sequalae following repetitive mild TBI. Thus, the investigative team has designed specific aims to: (Aim 1) define the role of neuronal p38 MAPK in driving neuroinflammation after rmTBI, including cytokine expression and microglial phenotype; (Aim 2) define the role of neuronal p38 MAPK in driving longer term cognitive outcomes up to 12 weeks post injury, test the ability of transient pharmacologic inhibition of p38 MAPK to protect cognitive outcomes, and determine if microglia mediate the effects of neuronal p38 MAPK on cognitive outcomes; (Aim 3) determine if neuronal p38 MAPK or a neuronally expressed vasomodulatory cytokine (IL-17) drive changes in CBF after repetitive mild TBI. The proposed work will be completed by a team with expertise in systems analysis of neural immune signaling (Wood), pre-clinical models of traumatic brain injury and measurement of CBF (Buckley), microglial phenotyping (Rangaraju) and mechanisms of cerebral blood flow regulation (Jo). Completion of these aims will yield unprecedented insight into the role of neuronal phospho-signaling in driving sequalae following repetitive mild TBI. Moreover, since this work will test a translationally relevant drug for inhibition of p38 MAPK, success of these aims will present a rapidly translatable approach to treatment of repetitive mild TBI.

项目摘要 轻度创伤性脑损伤（mTBI）每年影响数百万人，使10-40%的患者长期（>1 一个月）的身体、情感、心理和认知症状，有效的治疗策略 缺乏。此外，重复性mTBI（rmTBI）可导致不良反应的累积严重性和持续时间。 后果临床和临床前研究表明， 损伤后不能仅用生物力学冲击力来解释。潜在的损伤机制 重复性轻度创伤性脑损伤（rmTBI）后的神经系统症状知之甚少， 与更严重形式的TBI不同。伍德博士和巴克利博士（联合PI）最近共同努力， 发现神经元p38 MAPK磷酸化在预测有 rmTBI后认知功能更差。p38 MAPK是一种应激反应途径， TBI后小胶质细胞中的炎症作用。然而，对于神经元p38的作用， MAPK磷酸化在调节导致细胞和认知功能障碍的损伤反应中的作用 在TBI之后我们的总体假设是，p38 MAPK磷酸化，特别是在神经元内，驱动1） 细胞因子表达、小胶质细胞活化和脑血流量的急性变化，以及2）细胞因子表达、小胶质细胞活化和脑血流量的慢性变化。 rmTBI后小胶质细胞和认知缺陷。由于对神经元磷酸信号作用的了解有限， 在TBI后驱动这些神经炎症、认知和生理变化方面，本提案的目标是 扩大我们对p38 MAPK磷酸化在反复轻度脑损伤后脑后遗症中作用的认识， 创伤性脑损伤因此，研究小组设计了具体的目标：（目标1）确定神经元p38 MAPK的作用 在rmTBI后驱动神经炎症，包括细胞因子表达和小胶质细胞表型;（目的2） 确定神经元p38 MAPK在驱动损伤后长达12周的长期认知结果中的作用， 测试p38 MAPK的瞬时药理学抑制保护认知结果的能力，并确定 小胶质细胞是否介导神经元p38 MAPK对认知结果的影响;（目的3）确定神经元p38 MAPK是否介导神经元p38 MAPK对认知结果的影响。 p38 MAPK或神经元表达的血管调节细胞因子（IL-17）驱动重复给药后CBF的变化。 轻度创伤性脑损伤拟议的工作将由一个具有神经免疫系统分析专业知识的团队完成。 信号传导（Wood）、创伤性脑损伤的临床前模型和CBF测量（Buckley）、小胶质细胞 表型（Rangaraju）和脑血流调节机制（Jo）。实现这些目标将 对神经元磷酸信号在驱动重复性脑损伤后后遗症中的作用产生了前所未有的洞察力。 轻度创伤性脑损伤此外，由于这项工作将测试一种预防性相关药物对p38 MAPK的抑制作用，因此成功的 这些目标将提出一个快速翻译的方法来治疗反复轻度TBI。