Mechanisms of Circadian and Synaptic Dysfunction After Repetitive Mild TBI

重复性轻度 TBI 后昼夜节律和突触功能障碍的机制

• 批准号: 10418007
• 负责人: Jonathan Oren Lipton
• 金额: $ 236.62万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10418007
• 关键词: ARNTL gene; Acute; Address; Adolescence; Adolescent; Affect; Alzheimer' s Disease; Astrocytes; Automobile Driving; Biochemical; Biochemistry; Brain; Brain Concussion; Cells; Chemosensitization; Circadian Dysregulation; Circadian Rhythms; Clock protein; Closed head injuries; Cognition; Cognitive; Cognitive deficits; Complex; Cultured Cells; Data; Defect; Dementia; Development; Disease; Electrons; Endothelium; FRAP1 gene; Functional disorder; Genetic; Hippocampus (Brain); Human; IL1R1 gene; Impaired cognition; Impairment; In Vitro; Inflammation; Inflammatory; Injury; Interleukin-1; Interleukin-1 Receptors; Interleukin-1 beta; Knock-out; Lead; Learning; Life; Link; Mediating; Mediator of activation protein; Memory; Memory impairment; Modeling; Molecular; Mus; Nerve Degeneration; Neurodegenerative Disorders; Neuroimmune; Neurologic; Neurons; Outcome; Pathogenicity; Pathway interactions; Periodicity; Persons; Phosphorylation; Phosphotransferases; Physiological; Physiology; Post-Concussion Syndrome; Protein Isoforms; Proteins; Recording of previous events; Recovery; Regulation; Reporting; Resistance; Role; Signal Pathway; Signal Transduction; Sleep disturbances; Slice; Specificity; Synapses; Synaptic plasticity; Synaptosomes; TBI treatment; Tauopathies; Testing; Therapeutic; Time; Transgenic Organisms; War; Wild Type Mouse; Work; autocrine; brain cell; cell type; chronic traumatic encephalopathy; circadian; circadian pacemaker; combinatorial; epidemiology study; excitatory neuron; long term memory; mild traumatic brain injury; mouse model; new therapeutic target; novel; novel therapeutics; paracrine; presynaptic; prevent; response; synaptic function; tau Proteins; tau phosphorylation; tau-1; therapy design

Mild traumatic brain injury (mTBI) affects hundreds of millions of young people world-wide each year. Epidemiological studies link repetitive mTBI to dementia and neurodegenerative disease later in life, however causative mechanisms remain undefined. Disruption of circadian rhythms is a prominent manifestation of the post-concussive syndrome and has been associated with Alzheimer’s-like neurodegeneration but the mechanisms linking mTBI, neurodegeneration, and circadian rhythms is unknown, highlighting a key unmet need in mTBI and an unexplored therapeutic opportunity. We previously reported that IL-1 receptor-1 signaling is required for post-injury cognitive deficits in mTBI models, implicating inflammatory pathways as key pathogenic mechanisms. We hypothesized that there would be direct molecular connections between the circadian clock and neuroimmune signaling through the IL-1 receptor pathway. Our preliminary data show that repetitive mTBI induces phosphorylation of the key circadian clock protein BMAL1 in wild type but not IL-1R1-deficient mouse brain. Our ongoing work has identified a critical function for BMAL1 phosphorylation in the organization of presynaptic function and long-term memory. Our results lead to our hypothesis that repetitive mTBI induces synaptic dysfunction and cognitive deficits via IL-1R1-mediated hyperphosphorylation of BMAL1. In Aim 1, we will define how ILR1-mediated pBMAL1 signaling in response to mTBI corrupts the timing of synaptic function and impairs synaptic plasticity. In Aim 2, we will use combinatorial and complementary transgenic approaches including mouse models uniquely available to our groups, to define the cell types responsible for IL-1R-mediated signaling that culminate in cognitive dysfunction after mTBI. Finally, Aim 3 will define a novel signaling pathway by which IL-1-mediated hyperphosphorylation of pBMAL1 after mTBI results in dysfunctional regulation of key synaptic and neuronal kinases such as CaMKIIA with subsequent promulgation of tau-related aggregation and impaired synaptic plasticity. Successful completion of the Aims is expected to provide a cellular and molecular basis for repetitive mTBI-induced cognitive dysfunction and identify new therapeutic targets to alleviate sequelae of concussions and other forms of repetitive mTBI.

轻度创伤性脑损伤 (mTBI) 每年影响全球数亿年轻人。 然而，流行病学研究将重复性 mTBI 与晚年痴呆和神经退行性疾病联系起来 致病机制仍不明确。昼夜节律紊乱是昼夜节律紊乱的一个突出表现 脑震荡后综合症，并与阿尔茨海默病样神经变性有关，但 mTBI、神经退行性变和昼夜节律之间的联系机制尚不清楚，这凸显了一个关键的未满足需求 mTBI 和一个尚未探索的治疗机会。我们之前报道过 IL-1 受体 1 信号传导是 mTBI 模型中损伤后认知缺陷所需的，表明炎症途径是关键致病因素 机制。我们假设生物钟之间存在直接的分子联系 以及通过 IL-1 受体途径的神经免疫信号传导。我们的初步数据表明，重复性 mTBI 在野生型而非 IL-1R1 缺陷型小鼠中诱导关键生物钟蛋白 BMAL1 的磷酸化 脑。我们正在进行的工作已经确定了 BMAL1 磷酸化在组织中的关键功能 突触前功能和长期记忆。我们的结果得出我们的假设：重复性 mTBI 会导致 通过 IL-1R1 介导的 BMAL1 过度磷酸化导致突触功能障碍和认知缺陷。在目标 1 中，我们 将定义 ILR1 介导的 pBMAL1 信号如何响应 mTBI 破坏突触功能的时序 并损害突触可塑性。在目标 2 中，我们将使用组合和互补的转基因方法 包括我们小组独有的小鼠模型，以确定负责 IL-1R 介导的细胞类型 mTBI 后最终导致认知功能障碍的信号传导。最后，Aim 3 将定义一个新的信号通路 mTBI 后，IL-1 介导的 pBMAL1 过度磷酸化导致关键的调节功能失调 突触和神经元激酶，例如 CaMKIIA，随后发布 tau 相关聚集和 突触可塑性受损。目标的成功完成预计将提供细胞和分子 重复 mTBI 诱发的认知功能障碍的基础，并确定新的治疗靶点以减轻后遗症 脑震荡和其他形式的重复性 mTBI。