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Molecular, cellular and physiological mechanisms of the mammalian circadian clock

哺乳动物生物钟的分子、细胞和生理机制

基本信息

批准号：
10462479
负责人：
JOHN B HOGENESCH
金额：
$ 53.09万
依托单位：
CINCINNATI CHILDRENS HOSP MED CTR
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-05-01 至 2024-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10462479
关键词：
ARNTL gene Animal Testing Behavior Biochemical Biological Biological Assay Biological Clocks Biological Response Modifiers Brain Calcium Signaling Cell Nucleus Cell physiology Cells Circadian Rhythms Clustered Regularly Interspaced Short Palindromic Repeats Complex Cyclosporine Cytoplasm Data Development Drosophila genus Erinaceidae Feedback Genes Genetic Genetic Models Genetic Transcription Grant Human Hypothalamic structure Immunity Impairment Knock-out Knockout Mice Length Link Luciferases Malignant Neoplasms Mammals Mental Depression Modeling Molecular Motor Activity Mus NFAT Pathway Natural Immunity Nerve Degeneration Neuraxis Neurons Nuclear Translocation Output Oxidation-Reduction Pathway interactions Persons Pharmacology Phenotype Phosphoric Monoester Hydrolases Phosphotransferases Physiological Physiological Processes Physiology Play Presynaptic Terminals Process Proteins Proteolysis RNA Interference Regulation Repression Repressor Proteins Role Signal Transduction Signal Transduction Pathway Signaling Molecule Sleep Wake Cycle Slice System Testing Transcription Coactivator Untranslated RNA Work adaptive immunity alpha synuclein astrogliosis beta Karyopherins circadian circadian pacemaker conditional knockout fly high risk in vivo inhibitor knock-down member new therapeutic target oxidative damage protein TDP-43 protein complex scaffold shift work sleep regulation sound suprachiasmatic nucleus transcription factor

项目摘要

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.

项目总结/文摘

项目成果

期刊论文数量（56）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

A database of tissue-specific rhythmically expressed human genes has potential applications in circadian medicine.

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

Short-term exposure to intermittent hypoxia leads to changes in gene expression seen in chronic pulmonary disease.

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

A genome-wide screen identifies PAPP-AA-mediated IGFR signaling as a novel regulator of habituation learning.

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

Benchmark analysis of algorithms for determining and quantifying full-length mRNA splice forms from RNA-seq data.