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:
- 金额:$ 236.62万
- 依托单位:
- 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:
- 关键词:ARNTL geneAcuteAddressAdolescenceAdolescentAffectAlzheimer&aposs DiseaseAstrocytesAutomobile DrivingBiochemicalBiochemistryBrainBrain ConcussionCellsChemosensitizationCircadian DysregulationCircadian RhythmsClock proteinClosed head injuriesCognitionCognitiveCognitive deficitsComplexCultured CellsDataDefectDementiaDevelopmentDiseaseElectronsEndotheliumFRAP1 geneFunctional disorderGeneticHippocampus (Brain)HumanIL1R1 geneImpaired cognitionImpairmentIn VitroInflammationInflammatoryInjuryInterleukin-1Interleukin-1 ReceptorsInterleukin-1 betaKnock-outLeadLearningLifeLinkMediatingMediator of activation proteinMemoryMemory impairmentModelingMolecularMusNerve DegenerationNeurodegenerative DisordersNeuroimmuneNeurologicNeuronsOutcomePathogenicityPathway interactionsPeriodicityPersonsPhosphorylationPhosphotransferasesPhysiologicalPhysiologyPost-Concussion SyndromeProtein IsoformsProteinsRecording of previous eventsRecoveryRegulationReportingResistanceRoleSignal PathwaySignal TransductionSleep disturbancesSliceSpecificitySynapsesSynaptic plasticitySynaptosomesTBI treatmentTauopathiesTestingTherapeuticTimeTransgenic OrganismsWarWild Type MouseWorkautocrinebrain cellcell typechronic traumatic encephalopathycircadiancircadian pacemakercombinatorialepidemiology studyexcitatory neuronlong term memorymild traumatic brain injurymouse modelnew therapeutic targetnovelnovel therapeuticsparacrinepresynapticpreventresponsesynaptic functiontau Proteinstau phosphorylationtau-1therapy 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。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Jonathan Oren Lipton其他文献
Jonathan Oren Lipton的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('Jonathan Oren Lipton', 18)}}的其他基金
Investigating Circadian Mechanisms of Cellular Resilience: Rhythmic Condensates, Disorder, and Stress
研究细胞弹性的昼夜节律机制:节律凝聚、紊乱和压力
- 批准号:
10403440 - 财政年份:2020
- 资助金额:
$ 236.62万 - 项目类别:
Investigating Circadian Mechanisms of Cellular Resilience: Rhythmic Condensates, Disorder, and Stress
研究细胞弹性的昼夜节律机制:节律凝聚、紊乱和压力
- 批准号:
10614584 - 财政年份:2020
- 资助金额:
$ 236.62万 - 项目类别:
Sleep and Circadian Rhythms in Tuberous Sclerosis Complex
结节性硬化症的睡眠和昼夜节律
- 批准号:
8441512 - 财政年份:2012
- 资助金额:
$ 236.62万 - 项目类别:
Sleep and Circadian Rhythms in Tuberous Sclerosis Complex
结节性硬化症的睡眠和昼夜节律
- 批准号:
8609049 - 财政年份:2012
- 资助金额:
$ 236.62万 - 项目类别:
Sleep and Circadian Rhythms in Tuberous Sclerosis Complex
结节性硬化症的睡眠和昼夜节律
- 批准号:
8813606 - 财政年份:2012
- 资助金额:
$ 236.62万 - 项目类别:
Sleep and Circadian Rhythms in Tuberous Sclerosis Complex
结节性硬化症的睡眠和昼夜节律
- 批准号:
8224377 - 财政年份:2012
- 资助金额:
$ 236.62万 - 项目类别:
Sleep and Circadian Rhythms in Tuberous Sclerosis Complex
结节性硬化症的睡眠和昼夜节律
- 批准号:
9024595 - 财政年份:2012
- 资助金额:
$ 236.62万 - 项目类别:
相似海外基金
Acute senescence: a novel host defence counteracting typhoidal Salmonella
急性衰老:对抗伤寒沙门氏菌的新型宿主防御
- 批准号:
MR/X02329X/1 - 财政年份:2024
- 资助金额:
$ 236.62万 - 项目类别:
Fellowship
Transcriptional assessment of haematopoietic differentiation to risk-stratify acute lymphoblastic leukaemia
造血分化的转录评估对急性淋巴细胞白血病的风险分层
- 批准号:
MR/Y009568/1 - 财政年份:2024
- 资助金额:
$ 236.62万 - 项目类别:
Fellowship
Combining two unique AI platforms for the discovery of novel genetic therapeutic targets & preclinical validation of synthetic biomolecules to treat Acute myeloid leukaemia (AML).
结合两个独特的人工智能平台来发现新的基因治疗靶点
- 批准号:
10090332 - 财政年份:2024
- 资助金额:
$ 236.62万 - 项目类别:
Collaborative R&D
Cellular Neuroinflammation in Acute Brain Injury
急性脑损伤中的细胞神经炎症
- 批准号:
MR/X021882/1 - 财政年份:2024
- 资助金额:
$ 236.62万 - 项目类别:
Research Grant
STTR Phase I: Non-invasive focused ultrasound treatment to modulate the immune system for acute and chronic kidney rejection
STTR 第一期:非侵入性聚焦超声治疗调节免疫系统以治疗急性和慢性肾排斥
- 批准号:
2312694 - 财政年份:2024
- 资助金额:
$ 236.62万 - 项目类别:
Standard Grant
Combining Mechanistic Modelling with Machine Learning for Diagnosis of Acute Respiratory Distress Syndrome
机械建模与机器学习相结合诊断急性呼吸窘迫综合征
- 批准号:
EP/Y003527/1 - 财政年份:2024
- 资助金额:
$ 236.62万 - 项目类别:
Research Grant
FITEAML: Functional Interrogation of Transposable Elements in Acute Myeloid Leukaemia
FITEAML:急性髓系白血病转座元件的功能研究
- 批准号:
EP/Y030338/1 - 财政年份:2024
- 资助金额:
$ 236.62万 - 项目类别:
Research Grant
KAT2A PROTACs targetting the differentiation of blasts and leukemic stem cells for the treatment of Acute Myeloid Leukaemia
KAT2A PROTAC 靶向原始细胞和白血病干细胞的分化,用于治疗急性髓系白血病
- 批准号:
MR/X029557/1 - 财政年份:2024
- 资助金额:
$ 236.62万 - 项目类别:
Research Grant
ロボット支援肝切除術は真に低侵襲なのか?acute phaseに着目して
机器人辅助肝切除术真的是微创吗?
- 批准号:
24K19395 - 财政年份:2024
- 资助金额:
$ 236.62万 - 项目类别:
Grant-in-Aid for Early-Career Scientists
Collaborative Research: Changes and Impact of Right Ventricle Viscoelasticity Under Acute Stress and Chronic Pulmonary Hypertension
合作研究:急性应激和慢性肺动脉高压下右心室粘弹性的变化和影响
- 批准号:
2244994 - 财政年份:2023
- 资助金额:
$ 236.62万 - 项目类别:
Standard Grant














{{item.name}}会员




