The role of interferon regulatory factors in tanycytes during HFD-induced inflammation, obesity and glucose dysregulation
干扰素调节因子在 HFD 诱导的炎症、肥胖和葡萄糖失调过程中的作用
基本信息
- 批准号:10621286
- 负责人:
- 金额:$ 55.1万
- 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:2022-05-15 至 2027-02-28
- 项目状态:未结题
- 来源:
- 关键词:ATAC-seqAddressAdultAnatomyAstrocytesAtlasesAutopsyBehaviorBloodBlood - brain barrier anatomyBlood CirculationBrainCRISPR/Cas technologyCell CommunicationCell LineCell physiologyCellsCeramidesCirculationCommunicationComplexContinuous CapillaryCuesDataDesire for foodDietDisparateEndotheliumEpendymal CellEpidemicFaceFenestrated CapillaryFertilityGene Expression ProfilingGenesGenetic ModelsGenetic studyGlucoseHealthcare SystemsHigh Fat DietHomeostasisHumanHypothalamic structureIRF3 geneInfiltrationInflammationInflammatoryInflammatory ResponseInsulin ResistanceInterferon ActivationInterferonsLactationLifeLocationLoxP-flanked alleleMAPK8 geneMagnetic Resonance ImagingMediatingMediatorMetabolic dysfunctionMethodsMicrogliaModelingMolecularMolecular TargetMusNeuronsNutritionalObesityOvernutritionParticipantPathologicPathway AnalysisPathway interactionsPeripheralPharmacological TreatmentPhenotypePhysiologicalPhysiologyPlayPositioning AttributeProcessRNARegulationRegulatory ElementRodent ModelRoleSentinelSideSignal TransductionStreamStructure of nucleus infundibularis hypothalamiTLR4 geneTestingTherapeuticTissuesTranscriptional ActivationVentricularWeight GainWorkbrain parenchymacell typecombatconstitutive expressiondesignendoplasmic reticulum stressenergy balanceepigenomic profilingglucose metabolismimprovedinsulin sensitivityknockout genemedian eminencemetabolic phenotypeneurogenesisobesogenicpassive transportperipheral bloodprogenitorprogramsreceptorresponsesingle cell sequencingsingle nucleus RNA-sequencingsingle-cell RNA sequencingtranscriptome sequencing
项目摘要
Project Abstract
The arcuate nucleus-median eminence complex (Arc-ME) is an evolutionarily conserved region
of the hypothalamus that plays important roles in physiology and behavior, including control of
appetite, energy balance, insulin sensitivity, fertility and lactation. In rodent models, the initiation
of a high fat diet (HFD) rapidly induces inflammation specifically within Arc-ME, well in advance
of inflammation observed in peripheral tissues. Genetic studies disrupting this inflammation
protect from obesity, suggesting the inflammation is causal, and studies in humans show a
correlation between arcuate inflammation and obesity. The arcuate has a unique anatomical
relationship with bloodstream, as there is no classic endothelial Blood-Brain-Barrier (BBB)
separating it from the median eminence, which is invaginated by fenestrated capillaries that are
continuous with the peripheral circulation. Here, tanycytes, specialized ependymal cells found
lining the ventricular wall of the basal hypothalamus, extend elaborate processes that separate
the Arc and ME, thereby partitioning the ME, CSF, and brain parenchyma into distinct
compartments. Studies of hypothalamic inflammation have not previously addressed a role for
tanycytes, despite their unique localization. Using single cell RNA-seq, we observe that HFD
induces an interferon response pathway specifically in 2 tanycytes, the subpopulation that
contacts the peripheral circulation. We hypothesize that 2 tanycytes are sentinel cells that
respond to signals associated with HFD by upregulating an inflammatory gene program and
initiates hypothalamic inflammation. We propose to test this hypothesis by examining whether
genetic models in which the interferon response program is specifically induced or disrupted in
tanycytes is sufficient/necessary for induction of hypothalamic inflammation. We further propose
to define specific interferon regulatory factor targets by which tanycytes elicit inflammation using
a combination of transcriptional and epigenomic profiling within tanycytes and estimation of cell-
cell communication from single cell sequencing of our perturbed models. Together, these studies
will demonstrate a new role for tanycytes in initiating HFD-induced hypothalamic inflammation
and identify specific molecular targets that enable them to do so. As 2 tanycytes are located
outside of the BBB, they provide an attractive and specific target cell type modulating energy
homeostasis against which to design therapeutics to combat obesity.
项目摘要
弓状核-正中隆起复合体(Arc-ME)是一个进化上保守的区域
在生理和行为中起重要作用的下丘脑,包括控制
食欲、能量平衡、胰岛素敏感性、生育能力和泌乳。在啮齿动物模型中,
高脂饮食(HFD)的快速诱导炎症,特别是在Arc-ME内,
在外周组织中观察到的炎症。遗传学研究破坏这种炎症
防止肥胖,这表明炎症是因果关系,对人类的研究表明,
弓形炎症与肥胖之间的相关性。弓状肌具有独特的解剖学结构
与血流的关系,因为没有经典的内皮血脑屏障(BBB)
将其与正中隆起分开,正中隆起被有孔毛细血管内陷,
与外周循环相连。在这里,我们发现了伸长细胞,
衬在下丘脑基底的心室壁上,延伸出精细的过程,
Arc和ME,从而将ME、CSF和脑实质分成不同的区域,
隔间下丘脑炎症的研究以前没有解决的作用,
尽管它们有独特的定位,使用单细胞RNA-seq,我们观察到HFD
特异性地在β 2伸长细胞中诱导干扰素应答途径,
接触外周循环。我们假设,β 2伸长细胞是哨兵细胞,
通过上调炎症基因程序对HFD相关信号作出反应,
引发下丘脑炎症我们建议通过检查是否
干扰素应答程序被特异性诱导或破坏的遗传模型,
伸长细胞对于诱导下丘脑炎症是足够的/必需的。我们进一步建议
使用定义延伸细胞引发炎症的特定干扰素调节因子靶点
在伸长细胞内的转录和表观基因组谱分析的组合和细胞-
从我们的扰动模型的单细胞测序的细胞通信。这些研究一起
将证明伸长细胞在引发HFD诱导的下丘脑炎症中的新作用
并确定特定的分子目标,使他们能够这样做。由于102个伸长细胞位于
在BBB外,它们提供有吸引力的和特异性的靶细胞类型调节能量
体内平衡来设计治疗肥胖的方法。
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)
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Linus Tzu-Yen Tsai其他文献
Linus Tzu-Yen Tsai的其他文献
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{{ truncateString('Linus Tzu-Yen Tsai', 18)}}的其他基金
The role of interferon regulatory factors in tanycytes during HFD-induced inflammation, obesity and glucose dysregulation
干扰素调节因子在 HFD 诱导的炎症、肥胖和葡萄糖失调过程中的作用
- 批准号:
10446598 - 财政年份:2022
- 资助金额:
$ 55.1万 - 项目类别:
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