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

基本信息

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
项目类别：
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&apos 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

项目摘要

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）每年都会影响全球数亿年的年轻人。流行病学研究将重复MTBI与痴呆症和神经退行性疾病联系起来，但是病因机制仍然不确定。昼夜节律的破坏是脑震荡后综合征，与阿尔茨海默氏症的神经变性有关连接MTBI，神经变性和昼夜节律的机制未知，突出了关键的未满足需求在MTBI和意外的治疗机会中。我们先前报道了IL-1受体-1信号传导是 MTBI模型中伤害后认知缺陷所必需的，暗示炎症途径是关键的致病性机制。我们假设昼夜节律之间会有直接的分子连接通过IL-1受体途径传导神经免疫信号。我们的初步数据表明重复的mtbi 在野生型中诱导关键昼夜节律蛋白BMAL1的磷酸化，而不是IL-1R1缺陷小鼠脑。我们正在进行的工作已经确定了BMAL1磷酸化的关键功能突触前功能和长期记忆。我们的结果导致了我们的假设，即重复的MTBI影响通过IL-1R1介导的BMAL1的超磷酸化，突触功能障碍和认知缺陷。在AIM 1中，我们将定义ILR1介导的PBMAL1信号对MTBI的响应如何破坏突触功能的时间并损害合成可塑性。在AIM 2中，我们将使用组合和完整的转基因方法包括我们组独特可用的鼠标模型，以定义负责IL-1R介导的细胞类型信号表明MTBI后最终导致认知功能障碍。最后，AIM 3将定义一个新颖的信号通路 MTBI后，IL-1介导的PBMAL1的高磷酸化导致键调节功能失调突触和神经元激酶，例如CaMKIIA，随后颁布了与Tau相关的聚集和合成可塑性受损。预计成功完成目标将提供细胞和分子重复MTBI诱导的认知功能障碍的基础，并确定新的治疗靶标以减轻后遗症咨询和其他形式的重复MTBI。