THE ROLE OF PTEN IN MICROGLIAL PATHOBIOLOGY AFTER EXPOSURE TO REPETITIVE MILD TBI
PTEN 在反复轻度 TBI 暴露后微胶质病理学中的作用
基本信息
- 批准号:10683340
- 负责人:
- 金额:$ 16.34万
- 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:2022-08-15 至 2024-07-31
- 项目状态:已结题
- 来源:
- 关键词:AddressAlzheimer&aposs disease related dementiaAlzheimer&aposs disease riskAnimal ModelAstrocytesAutomobile DrivingAutophagocytosisAutopsyBiochemical MarkersBioenergeticsBlood - brain barrier anatomyBlood VesselsCell SurvivalCellsChronicClinicalClinical TrialsConsultationsCre-LoxPCytokine SignalingDataDevelopmentDiseaseDisease associated microgliaEnsureEventExposure toFutureGenesGoalsHumanInflammationInflammatoryInflammatory ResponseInjuryInterventionInvestigationLearningLipidsMediatingMemoryMicrogliaModelingMolecular BankMyeloid CellsNerve DegenerationNervous System TraumaNeurodegenerative DisordersNeurologic DeficitNeurologic DysfunctionsNeuronsOutcomePIK3CG genePTEN genePathogenesisPathologyPatientsPerformancePhenotypePhosphoric Monoester HydrolasesPilot ProjectsPlayPre-Clinical ModelResearch DesignRetrospective StudiesRisk FactorsRoleSensorimotor functionsSignal TransductionSpecificitySynapsesTBI PatientsTamoxifenTherapeuticTimeastrogliosisaxon injurybrain cellcell typedensityfunctional outcomesgenetic signaturehuman modelinhibitorlipid metabolismmild traumatic brain injurymouse modelneurobehavioralneuroinflammationneuropathologyneuroprotectionnew therapeutic targetnovelpharmacologicpre-clinicalpreventprophylacticresponseresponse to injurysingle cell analysistau Proteinstherapeutic targettimelinetranscriptomicstranslational potentialtreatment strategy
项目摘要
Repetitive mild traumatic brain injury (r-mTBI) is one of the strongest risk factors for developing
neurodegenerative diseases. To date, no disease modifying therapies have been developed to prevent the long-
term consequences of TBI. There is a need to advance our current understanding of the cellular mechanisms
driving the long-term neurological deficits after TBI, as this could lead to the identification of novel therapeutic
targets. Neuroinflammation mediated by resident microglia is a common feature of human and animal models
of TBI. Factors governing the propagation and persistence of disease associated microglial responses in the
chronic sequelae of TBI remain elusive. We have established a mouse model of r-mTBI that recapitulates many
features of human TBI and thus represents a translationally relevant preclinical platform. From this model we
have generated a molecular library of microglia gene profiles, at a range of timepoints post-injury that provides
a unique and detailed time-course of the microglial neuroinflammatory response to r-mTBI. Particularly, we
reveal deficits in energy bioenergetics, cytokine signaling, lipid metabolism, and a pro-inflammatory signature
of microglia at chronic timepoints, which appear to be driven by the activation of Phosphatase and Tensin
Homolog (PTEN) signaling. PTEN is a lipid phosphatase that antagonizes phosphatidylinositol 3-Kinase
signaling, a critical node vital for regulating cell survival, energy bioenergetics, autophagy and inflammation.
PTEN is highly expressed in myeloid cells, and its dysregulation can trigger the activation of inflammatory
responses. Multiple cell types express PTEN, thus PTEN inhibitors lack the specificity needed to target PTEN
signaling in microglia. In a pilot study, we have shown that PTEN deletion in myeloid cells after 1 mo
dampens disease associated microglial responses and proinflammatory signature in our model. In this
new application, we plan to extend these studies to further clarify the role of PTEN in regulating microglia
responses in the context of TBI and demonstrate whether microglia specific PTEN deletion can mitigate TBI
mediated neuroinflammation/neurodegeneration and chronic functional outcomes. We will compare TBI-
dependent responses in the presence or absence of PTEN deletion to reveal microglial specific targets that
correlate with favorable outcomes after r-mTBI and represent novel therapeutic targets. We will achieve this by
utilizing a tamoxifen inducible mouse model that will specifically target PTEN deletion in microglia and not
other myeloid cells (Hexbcre+/PTENfl/fl). We will induce PTEN deletion using three therapeutic time-windows
(i.e., pre-injury, early and delayed), and examine functional and pathobiological outcomes, scRNAseq profiles
and functional activities of microglia at 6 mo post-injury. Our goal is to clarify the role of PTEN as a negative
regulator of microglial pathobiology in the chronic sequelae of r-mTBI, and to identify unique gene signatures
and reparative mechanisms in microglia induced by PTEN deletion that can be explored as novel microglial
specific targets in TBI and other neurodegenerative diseases where neuroinflammation is a critical contributor.
重复的轻度外伤性脑损伤(R-MTBI)是发展最强的风险因素之一
神经退行性疾病。迄今为止,尚未开发任何修改疾病以防止长期
TBI的术语后果。有必要提高我们当前对细胞机制的理解
在TBI之后驱动长期神经缺陷,因为这可能导致新的治疗性鉴定
目标。居民小胶质细胞介导的神经炎症是人类和动物模型的共同特征
tbi。管理疾病相关小胶质反应的传播和持续性的因素
TBI的慢性后遗症仍然难以捉摸。我们已经建立了R-MTBI的鼠标模型,该模型概括了许多
人类TBI的特征,因此代表了翻译相关的临床前平台。从这个模型我们
在受伤后的一系列时间点上生成了小胶质细胞基因剖面的分子库
对R-MTBI的小胶质神经炎症反应的独特而详细的时间课。特别是我们
揭示能量生物能学,细胞因子信号传导,脂质代谢和促炎性特征的缺陷
在慢性时点的小胶质细胞,这似乎是由磷酸酶和tensin的激活驱动的
同源物(PTEN)信号传导。 PTEN是一种脂质磷酸酶,拮抗磷脂酰肌醇3-激酶
信号传导是调节细胞存活,能量生物能,自噬和炎症至关重要的关键节点。
PTEN在髓样细胞中高度表达,其失调会触发炎症的激活
回答。多种细胞类型表达PTEN,因此PTEN抑制剂缺乏靶向PTEN所需的特异性
小胶质细胞中的信号传导。在一项初步研究中,我们表明1 mo后髓样细胞中的PTEN缺失
在我们的模型中抑制疾病相关的小胶质反应和促炎性签名。在这个
新应用,我们计划扩展这些研究,以进一步阐明PTEN在调节小胶质细胞中的作用
在TBI的背景下的响应,并证明小胶质细胞特定的PTEN缺失是否可以减轻TBI
介导的神经炎症/神经变性和慢性功能结果。我们将比较tbi-
在存在或不存在PTEN缺失的情况下,依赖反应揭示了小胶质细胞的特定目标
与R-MTBI后的有利结果相关,并代表新的治疗靶标。我们将通过
利用他莫昔芬诱导小鼠模型,该模型将专门针对小胶质细胞中的PTEN缺失
其他髓样细胞(hexbcre+/ptenfl/fl)。我们将使用三个治疗时光降低PTEN删除
(即,受伤前,早期和延迟),并检查功能和病理学结果,Scrnaseq概况
小胶质细胞在伤害后6月的功能活动。我们的目标是阐明PTEN的作用
R-MTBI慢性后遗症小胶质病理生物学调节剂,并鉴定独特的基因特征
PTEN缺失引起的小胶质细胞中的修复机制,可以作为新的小胶质细胞探讨
TBI和其他神经退行性疾病的特定靶标是神经炎症是关键的重要因素。
项目成果
期刊论文数量(0)
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Joseph O Ojo其他文献
Joseph O Ojo的其他文献
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{{ truncateString('Joseph O Ojo', 18)}}的其他基金
The role of PPARγ in astrocyte pathobiology after exposure to repetitive mild traumatic brain injury
PPARγ 在重复性轻度脑外伤后星形胶质细胞病理学中的作用
- 批准号:
10739968 - 财政年份:2023
- 资助金额:
$ 16.34万 - 项目类别:
THE ROLE OF PTEN IN MICROGLIAL PATHOBIOLOGY AFTER EXPOSURE TO REPETITIVE MILD TBI
PTEN 在反复轻度 TBI 暴露后微胶质病理学中的作用
- 批准号:
10511758 - 财政年份:2022
- 资助金额:
$ 16.34万 - 项目类别:
The role of PPARγ in microglia pathobiologyafter exposure to repetitive mild traumatic brain injury
重复性轻度创伤性脑损伤后 PPARγ 在小胶质细胞病理学中的作用
- 批准号:
10557217 - 财政年份:2022
- 资助金额:
$ 16.34万 - 项目类别:
The role of PPARγ in microglia pathobiologyafter exposure to repetitive mild traumatic brain injury
重复性轻度创伤性脑损伤后 PPARγ 在小胶质细胞病理学中的作用
- 批准号:
10355038 - 财政年份:2022
- 资助金额:
$ 16.34万 - 项目类别:
Influence of APOE4 genotype on microglial pathobiology and tau pathology after repetitive mTBI
APOE4 基因型对重复 mTBI 后小胶质细胞病理学和 tau 病理学的影响
- 批准号:
10575479 - 财政年份:2022
- 资助金额:
$ 16.34万 - 项目类别:
Influence of APOE genotype on cerebrovascular cell pathobiology in AD, and the contribution of microglia inflammation
APOE基因型对AD脑血管细胞病理学的影响以及小胶质细胞炎症的贡献
- 批准号:
10289340 - 财政年份:2021
- 资助金额:
$ 16.34万 - 项目类别:
Influence of APOE genotype on cerebrovascular cell pathobiology in AD, and the contribution of microglia inflammation
APOE基因型对AD脑血管细胞病理学的影响以及小胶质细胞炎症的贡献
- 批准号:
10468189 - 财政年份:2021
- 资助金额:
$ 16.34万 - 项目类别:
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