Molecular, cellular and physiological mechanisms of the mammalian circadian clock
Molecular, cellular and physiological mechanisms of the mammalian circadian clock
批准号:
10462479
负责人:
JOHN B HOGENESCH
金额:
$53.09万
依托单位国家:
美国
项目类别:
财政年份:
2007
资助国家:
美国
项目状态:
已结题
起止时间:
2007-05-01 至 2024-02-29
关键词:
ARNTL geneAnimal TestingBehaviorBiochemicalBiologicalBiological AssayBiological ClocksBiological Response ModifiersBrainCalcium SignalingCell NucleusCell physiologyCellsCircadian RhythmsClustered Regularly Interspaced Short Palindromic RepeatsComplexCyclosporineCytoplasmDataDevelopmentDrosophila genusErinaceidaeFeedbackGenesGeneticGenetic ModelsGenetic TranscriptionGrantHumanHypothalamic structureImmunityImpairmentKnock-outKnockout MiceLengthLinkLuciferasesMalignant NeoplasmsMammalsMental DepressionModelingMolecularMotor ActivityMusNFAT PathwayNatural ImmunityNerve DegenerationNeuraxisNeuronsNuclear TranslocationOutputOxidation-ReductionPathway interactionsPersonsPharmacologyPhenotypePhosphoric Monoester HydrolasesPhosphotransferasesPhysiologicalPhysiological ProcessesPhysiologyPlayPresynaptic TerminalsProcessProteinsProteolysisRNA InterferenceRegulationRepressionRepressor ProteinsRoleSignal TransductionSignal Transduction PathwaySignaling MoleculeSleep Wake CycleSliceSystemTestingTranscription CoactivatorUntranslated RNAWorkadaptive immunityalpha synucleinastrogliosisbeta Karyopherinscircadiancircadian pacemakerconditional knockoutflyhigh riskin vivoinhibitorknock-downmembernew therapeutic targetoxidative damageprotein TDP-43protein complexscaffoldshift worksleep regulationsoundsuprachiasmatic nucleustranscription factor
中文摘要
项目摘要/摘要
生物钟调节生理和行为的许多方面。这些节奏是
由下丘脑视交叉上核(SCN)的主时钟协调。这
核心时钟由转录/翻译负反馈环组成,其中
转录激活因子BMAL1/CLOCK调节其自身抑制因子的表达
PER和CORT蛋白。这一压抑步骤是至关重要的,因为没有它,就没有节奏。钥匙
抑制过程中的步骤是PER/CREY蛋白复合体的协调易位
从细胞质到细胞核。最近,我们发现同一个NRON复合体
调节NFAT通路的转位,也调节PER/CRY的转位
复杂的昼夜节律时钟功能。NFAT途径调节发育,但也是先天的
以及外周和中枢神经系统的适应性免疫。这个NRON复合体是
由信号分子组成,例如CSNK1e、GSK3B和DYRK1(已知的时钟蛋白),但是
还有支架(IQGAP1,ncRNA NRON),蛋白质分解(PSMD11,CUL4B,UREB1),以及
核易位(KPNB1、CSE1L、TNPO1)。在人类细胞中使用遗传学
果蝇,我们已经证明了这些成分中的大多数都改变了周期长度,或者是
时钟功能齐全(KPNB1、PSMD11)。此外,药理上的微扰
NFAT通路改变SCN的生理和昼夜节律功能。在这里,我们寻求更好地
通过了解其生化和细胞生物学来理解这一关键的抑制步骤
机制,研究SCN中两条通路之间的串扰,并生成一套
用遗传模型来描述这些基因在调节SCN时钟和
睡眠/唤醒周期。这项工作将在NFAT调节的细胞之间提供第一个广泛的联系
和生理过程,包括大脑中的免疫力和核心时钟功能
管理行为和相关的生理。
英文摘要
PROJECT SUMMARY/ABSTRACT
The circadian clock regulates many aspects of physiology and behavior. These rhythms are
coordinated by the master clock in the suprachiasmatic nuclei (SCN) of the hypothalamus. This
core clock is composed of a transcriptional/translational negative feedback loop, where
transcriptional activators BMAL1/CLOCK regulate the expression of their own repressors, the
PER and CRY proteins. This repression step is critical, as without it, there's no rhythm. The key
step in the repression process is coordinated translocation of the PER/CRY protein complex
from the cytoplasm to the nucleus. Recently, we've found that the same NRON complex that
regulates translocation of the NFAT pathway, also regulates the translocation of the PER/CRY
complex and circadian clock function. The NFAT pathway regulates development but also innate
and adaptive immunity in the periphery and the central nervous system. This NRON complex is
comprised of signaling molecules, e.g. CSNK1e, GSK3B, and DYRK1 (known clock kinases), but
also scaffolding (IQGAP1, the ncRNA NRON), proteolysis (PSMD11, CUL4B, UREB1), and
nuclear translocation (KPNB1, CSE1L, TNPO1). Using genetics in human cells and in
Drosophila, we've shown that most of these components alter period length or are required for
clock function altogether (KPNB1, PSMD11). Further, pharmacological perturbation of the
NFAT pathway alters SCN physiology and circadian function. Here, we seek to better
understand this key repression step by understanding its biochemical and cell biological
mechanisms, study the cross talk between the two pathways in the SCN, and generate a suite of
genetic models to characterize the role of these genes in modulating the SCN clock and the
sleep/wake cycle. This work will provide the first broad linkage between NFAT-regulated cell
and physiological processes including immunity in the brain and core clock function that
governs behavior and associated physiologies.
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DOI:
10.1126/scitranslmed.aat8806
发表时间:
2018-09-12
期刊:
Science translational medicine
影响因子:
17.1
作者:
[Ruben MD, Wu G, Smith DF, Schmidt RE, Francey LJ, Lee YY, Anafi RC, Hogenesch JB]
通讯作者:
Hogenesch JB
A new view of transcriptome complexity and regulation through the lens of local splicing variations.
DOI:
10.7554/elife.11752
发表时间:
2016-02-01
期刊:
eLife
影响因子:
7.7
作者:
[Vaquero-Garcia J, Barrera A, Gazzara MR, González-Vallinas J, Lahens NF, Hogenesch JB, Lynch KW, Barash Y]
通讯作者:
Barash Y
DOI:
10.7554/elife.63003
发表时间:
2021-02-18
期刊:
eLife
影响因子:
7.7
作者:
[Wu G, Lee YY, Gulla EM, Potter A, Kitzmiller J, Ruben MD, Salomonis N, Whitsett JA, Francey LJ, Hogenesch JB, Smith DF]
通讯作者:
Smith DF
DOI:
10.1016/j.neuron.2015.02.025
发表时间:
2015-03-18
期刊:
NEURON
影响因子:
16.2
作者:
[Wolman, Marc A., Jain, Roshan A., Marsden, Kurt C., Bell, Hannah, Skinner, Julianne, Hayer, Katharina E., Hogenesch, John B., Granato, Michael]
通讯作者:
Granato, Michael
DOI:
10.1093/bioinformatics/btv488
发表时间:
2015-12-15
期刊:
Bioinformatics (Oxford, England)
影响因子:
--
作者:
[Hayer KE, Pizarro A, Lahens NF, Hogenesch JB, Grant GR]
通讯作者:
Grant GR
共 31 条
Molecular, Cellular and Physiological Mechanisms of the Mammalian Circadian Clock
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批准号:7414723
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项目类别:
-
资助金额:$46.9万
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财政年份:2007
-
负责人:JOHN B HOGENESCH
-
依托单位:
Molecular, Cellular and Physiological Mechanisms of the Mammalian Circadian Clock
-
批准号:8054360
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项目类别:
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资助金额:$48.35万
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财政年份:2007
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负责人:JOHN B HOGENESCH
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依托单位:
Molecular, cellular and physiological mechanisms of the mammalian circadian clock
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批准号:9349043
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项目类别:
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资助金额:$38.68万
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财政年份:2007
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负责人:JOHN B HOGENESCH
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依托单位:
Molecular, Cellular and Physiological Mechanisms of the Mammalian Circadian Clock
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批准号:7318271
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项目类别:
-
资助金额:$44.09万
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财政年份:2007
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负责人:JOHN B HOGENESCH
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依托单位:
Molecular, cellular and physiological mechanisms of the mammalian circadian clock
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批准号:8640983
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项目类别:
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资助金额:$55.87万
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财政年份:2007
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负责人:JOHN B HOGENESCH
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依托单位:
Molecular, cellular and physiological mechanisms of the mammalian circadian clock
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批准号:8328020
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项目类别:
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资助金额:$62.22万
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财政年份:2007
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负责人:JOHN B HOGENESCH
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依托单位:
Molecular, cellular and physiological mechanisms of the mammalian circadian clock
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批准号:8434164
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项目类别:
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资助金额:$53.82万
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财政年份:2007
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负责人:JOHN B HOGENESCH
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依托单位:
Molecular, Cellular and Physiological Mechanisms of the Mammalian Circadian Clock
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批准号:7591666
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项目类别:
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资助金额:$51.0万
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财政年份:2007
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负责人:JOHN B HOGENESCH
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依托单位:
Molecular, Cellular and Physiological Mechanisms of the Mammalian Circadian Clock
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批准号:7802070
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项目类别:
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资助金额:$48.33万
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财政年份:2007
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负责人:JOHN B HOGENESCH
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依托单位:
A Dual Transcriptional and High Content Assay for Cryptochrome
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批准号:7170097
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项目类别:
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资助金额:$19.63万
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财政年份:2006
-
负责人:JOHN B HOGENESCH
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依托单位:
Core O: HIGH THROUGHPUT SEQUENCING
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批准号:8516107
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项目类别:
-
资助金额:$33.56万
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财政年份:--
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负责人:JOHN B HOGENESCH
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依托单位:
Core O: HIGH THROUGHPUT SEQUENCING
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批准号:8689171
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项目类别:
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资助金额:$44.14万
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财政年份:--
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负责人:JOHN B HOGENESCH
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依托单位:
Core O: HIGH THROUGHPUT SEQUENCING
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批准号:8847394
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项目类别:
-
资助金额:$44.14万
-
财政年份:--
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负责人:JOHN B HOGENESCH
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依托单位:
Core O: HIGH THROUGHPUT SEQUENCING
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批准号:9069509
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项目类别:
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资助金额:$44.14万
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财政年份:--
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负责人:JOHN B HOGENESCH
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依托单位:
海外基金