THE ROLE OF DORSOMEDIAL HYPOTHALAMIC NEURONS IN MAMMALIAN AGING AND LONGEVITY
THE ROLE OF DORSOMEDIAL HYPOTHALAMIC NEURONS IN MAMMALIAN AGING AND LONGEVITY
批准号:
9927545
负责人:
SHIN-ICHIRO IMAI
金额:
$31.26万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
2011
资助国家:
美国
项目状态:
已结题
起止时间:
2011-05-15 至 2022-04-30
关键词:
AddressAdipose tissueAffectAgeAgingAnabolismApplications GrantsBindingBody TemperatureCommunicationComplementary DNADefectEnzymesExhibitsExpression ProfilingFamilyFeedbackFunctional disorderGene ExpressionGenesGenetic TranscriptionHormonesHumanHypothalamic structureInjectionsInterventionKnockout MiceLateral Hypothalamic NucleusLongevityMaintenanceMammalsMetabolicMusMuscle MitochondriaNeuronsObesityOutcomeOxygen ConsumptionPhenotypePhysical activityPhysiologicalPlayPreventive InterventionProcessRegulationResearchResearch ProposalsRodentRoleSIRT1 geneSignal PathwaySir2-like DeacetylasesSkeletal MuscleSubfamily lentivirinaeTherapeutic InterventionTissuesagedanti aginghistone methyltransferaseinsightknock-downmembermimicrynovelosteoinductive factoroverexpressionselective expressionsleep quality
中文摘要
最近的研究表明,下丘脑起着高级“衰老控制中心”的作用,
对抗年龄相关的病理生理变化,从而促进长寿
哺乳动物。我们的研究小组证明了哺乳动物依赖NAD的蛋白去乙酰基酶
SIRT1在下丘脑,特别是下丘脑背内侧核和外侧核(DMH和
促黄体生成素(Lh)对抵消与年龄相关的生理衰退和延长寿命至关重要
在老鼠身上。在DMH中,SIRT1及其结合伙伴Nkx2-1高度共存,使我们能够识别出
DMH神经元的特定亚群,即SIRT1/Nkx2-1双阳性神经元。最近,我们有
鉴定了一组在这些SIRT1/Nkx2-1双阳性DMH神经元中特异表达的基因。
其中一个基因是Prdm13,它编码PR结构域转录家族的一个成员。
监管者。Prdm13是SIRT1和Nkx2-1调控的下游靶基因之一。
DMH。DMH特异性Prdm13基因敲除的小鼠表现出睡眠质量下降,肥胖增加,
脂肪NAMPT的还原,脂肪分泌的一种关键的NAD生物合成酶
组织来远程调节下丘脑功能。另一方面,我们发现DMH-
甲状腺激素释放激素(TRH)基因的特异性敲除,另一个基因高度和
选择性表达于SIRT1/Nkx2-1双阳性DMH神经元,导致骨骼缺陷
肌肉线粒体基因表达、特异性肌动因子表达和体力活动。这些
结果提示,SIRT1/Nkx2-1双阳性DMH神经元至少含有两种功能
不同的神经元亚群,即Prdm13和TRH阳性神经元,并且每个
亚群调节下丘脑和脂肪之间不同的组织间反馈环
组织或骨骼肌。在这项研究计划中,我们将广泛调查生理学
这两个组织间反馈环的重要性。我们亦会研究是否维持
这些反馈环的活动可以抵消与年龄相关的病理生理变化和
有可能延长小鼠的寿命。拟议研究的预期结果将使
对我们理解哺乳动物衰老和长寿的系统调控产生了重大影响。
英文摘要
Recent studies demonstrate that the hypothalamus functions as a high-order “control center of aging”,
counteracting age-associated pathophysiological changes and thereby promoting longevity in
mammals. Our group demonstrated that the mammalian NAD+-dependent protein deacetylase
SIRT1 in the hypothalamus, particularly the dorsomedial and lateral hypothalamic nuclei (DMH and
LH, respectively), is critical to counteract age-associated physiological decline and promote longevity
in mice. In the DMH, SIRT1 and its binding partner Nkx2-1 highly colocalize, allowing us to identify a
specific subset of DMH neurons, namely, SIRT1/Nkx2-1-double positive neurons. Recently, we have
identified a set of genes specifically expressed in these SIRT1/Nkx2-1-double positive DMH neurons.
One of these genes is Prdm13, which encodes a member of the PR domain family of transcriptional
regulators. Prdm13 is one of the downstream target genes regulated by SIRT1 and Nkx2-1 in the
DMH. DMH-specific Prdm13-knockdown mice exhibit decreased sleep quality, increased adiposity,
and reduction in adipose Nampt, a key systemic NAD+ biosynthetic enzyme secreted from adipose
tissue to remotely regulate hypothalamic function. On the other hand, we found that the DMH-
specific knockdown of the thyrotoropin-releasing hormone (Trh) gene, another gene highly and
selectively expressed in the SIRT1/Nkx2-1-double positive DMH neurons, caused defects in skeletal
muscle mitochondrial gene expression, specific myokine expression, and physical activity. These
results suggest that SIRT1/Nkx2-1-double positive DMH neurons contain at least two functionally
distinct neuronal subpopulations, namely, Prdm13- and Trh-positive neurons, and that each
subpopulation regulates distinct inter-tissue feedback loops between the hypothalamus and adipose
tissue or skeletal muscle. In this research proposal, we will extensively investigate the physiological
importance of these two inter-tissue feedback loops. We will also examine whether maintaining the
activity of these feedback loops can counteract age-associated pathophysiological changes and
possibly extend lifespan in mice. The anticipated outcome from the proposed research will make a
significant impact to our understanding of the systemic regulation of aging and longevity in mammals.
期刊论文(2)
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会议论文
eNAMPT-mediated adipo-hypothalamic communication for NAD+ production and aging
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批准号:10394342
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项目类别:
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资助金额:$32.29万
-
财政年份:2014
-
负责人:SHIN-ICHIRO IMAI
-
依托单位:
eNAMPT-mediated adipo-hypothalamic communication for NAD+ production and aging
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批准号:9922842
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项目类别:
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资助金额:$32.27万
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财政年份:2014
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负责人:SHIN-ICHIRO IMAI
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依托单位:
ENAMPT-MEDIATED ADIPO-HYPOTHALAMIC COMMUNICATION FOR NAD+ PRODUCTION AND AGING
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批准号:8745156
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项目类别:
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资助金额:$30.75万
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财政年份:2014
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负责人:SHIN-ICHIRO IMAI
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依托单位:
eNAMPT-mediated adipo-hypothalamic communication for NAD+ production and aging
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批准号:10160728
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项目类别:
-
资助金额:$32.29万
-
财政年份:2014
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负责人:SHIN-ICHIRO IMAI
-
依托单位:
ENAMPT-MEDIATED ADIPO-HYPOTHALAMIC COMMUNICATION FOR NAD+ PRODUCTION AND AGING
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批准号:9260757
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项目类别:
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资助金额:$31.26万
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财政年份:2014
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负责人:SHIN-ICHIRO IMAI
-
依托单位:
eNAMPT-mediated adipo-hypothalamic communication for NAD+ production and aging
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批准号:10612762
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项目类别:
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资助金额:$32.29万
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财政年份:2014
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负责人:SHIN-ICHIRO IMAI
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依托单位:
SIRT1-MEDIATED CENTRAL ADAPTATION TO DIET RESTRICTION
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批准号:8254383
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项目类别:
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资助金额:$31.16万
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负责人:SHIN-ICHIRO IMAI
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依托单位:
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批准号:8661664
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项目类别:
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资助金额:$31.16万
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财政年份:2011
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负责人:SHIN-ICHIRO IMAI
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依托单位:
SIRT1-MEDIATED CENTRAL ADAPTATION TO DIET RESTRICTION
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批准号:8840861
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项目类别:
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资助金额:$30.23万
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财政年份:2011
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负责人:SHIN-ICHIRO IMAI
-
依托单位:
SIRT1-MEDIATED CENTRAL ADAPTATION TO DIET RESTRICTION
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批准号:8104868
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项目类别:
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资助金额:$31.16万
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财政年份:2011
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负责人:SHIN-ICHIRO IMAI
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依托单位:
SIRT1-MEDIATED CENTRAL ADAPTATION TO DIET RESTRICTION
-
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项目类别:
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财政年份:2011
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负责人:SHIN-ICHIRO IMAI
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依托单位:
Mammalian Sir2 Function in Pancreatic Beta Cells
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依托单位:
MAMMALIAN SIR2 FUNCTION IN PANCREATIC BETA CELLS
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财政年份:2004
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负责人:SHIN-ICHIRO IMAI
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依托单位:
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财政年份:2004
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依托单位:
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资助金额:$29.65万
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财政年份:2004
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依托单位:
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项目类别:
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资助金额:$30.25万
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财政年份:2004
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负责人:SHIN-ICHIRO IMAI
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依托单位:
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依托单位:
海外基金