Understanding the Gene Regulatory Mechanisms That Underlie Age-Induced Changes in the Circadian System and Neurodegeneration
Understanding the Gene Regulatory Mechanisms That Underlie Age-Induced Changes in the Circadian System and Neurodegeneration
批准号:
10404992
负责人:
David Anthony Hendrix
金额:
$36.14万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
2018
资助国家:
美国
项目状态:
已结题
起止时间:
2018-09-30 至 2024-05-31
关键词:
ATAC-seqAffectAgeAge of OnsetAgingAlzheimer&aposs DiseaseAlzheimer&aposs disease related dementiaAnimal ModelAutomobile DrivingAutopsyBehaviorBehavioralBindingBiologicalBiological MarkersBiology of AgingBrainCell physiologyChIP-seqChromatinChronobiologyCircadian DysregulationCircadian RhythmsClinical ResearchComputational BiologyComputer ModelsDNA BindingDataDementiaDiseaseDrosophila genusElderlyEpigenetic ProcessErythroidEventGene ExpressionGene Expression RegulationGenesGeneticGenetic TranscriptionGenomeGenomicsHeadHealthHeat shock factorHomeostasisHumanHyperoxiaHypoxia Inducible FactorIndividualKnock-outLeadLife Cycle StagesLongevityMammalsMeasurementMeasuresMicroRNAsMolecularMusNerve DegenerationNeurodegenerative DisordersNeuronsNeurophysiology - biologic functionNuclearOutputOxidative StressPathologyPathway interactionsPatientsPatternPeriodicityPersonsPhenocopyPhysiological ProcessesPlayPost-Transcriptional RegulationPredispositionPublicationsPublishingRNA InterferenceRNA Polymerase IIRegulator GenesRodentRoleSleepSmall RNAStressSystemSystems BiologyTestingTimeWorkage relatedage related neurodegenerationbasebiological adaptation to stresscircadiancircadian pacemakercircadian transcriptomecombatdata modelingflexibilityflyfollow-upgenetic manipulationgenome-widegenomic datahealthy agingheat shock transcription factorin vivo evaluationinnovationinsightkinetic modelnetwork modelsnoveloverexpressionoxidative damagepre-clinicalpredictive modelingpreventpromoterresponsetooltranscription factortranscriptometranscriptome sequencing
中文摘要
项目总结:
英文摘要
PROJECT SUMMARY:
The circadian system is an important network hub coordinating cellular functions and
homeostasis. Age-related alterations in the human circadian system are implicated in
Alzheimer’s and other neuronal pathologies. Recent evidence in fruit flies and mice suggests
correlation between disrupted rhythms and neurodegeneration; however, very little is known
about mechanisms involved. To investigate these mechanisms, we compared circadian
transcriptome in heads of young and old Drosophila using RNA-seq. We found that several
genes, early-life cyclers (ELCs), that were expressed in young flies in a rhythmic fashion lose
cycling pattern to become constitutively low or high in old flies. We also uncovered a group of
genes, which we termed late life cyclers (LLCs), that were low and arrhythmic in heads of young
flies but became strongly rhythmic in heads of old flies. This group contains known stress-
responsive genes that are induced in young flies in response to oxidative stress or hyperoxia.
Based on these findings from our recently published data, we hypothesize that the circadian
system is rewired during aging through a combination of alterations in inputs from, and outputs
to, stress-response pathways, and changes in post-transcriptional regulation by age-altered
microRNA expression. Because of the connections between the circadian system and
neurodegeneration, we expect some of these changes could be harmful for neuronal heath, and
others could be part of a protective mechanism. In Aim 1, we will measure genome-wide binding
of the core circadian transcription factors (TFs) CLK and CYC, stress responsive TFs, and RNA
Polymerase II through ChIP-Seq and identify age-specific binding events that could be
responsible for these regulatory changes. In addition, we will perform ATAC-seq to measure
chromatin accessibility. In Aim 2, we will develop network models of gene regulation by
combining this new data, along with our existing RNA-seq data and forthcoming small RNA-seq
data. We will build computational models and analyze genomic data to create a mechanistic
understanding of the epigenetic changes leading to the observed age-onset changes in diurnal
expression patterns. By comparing the networks that we will build for young and old flies, we will
be able to identify candidate regulators of aging, neurodegeneration (CRANs) that we will follow
up on. In Aim 3, we will study the role of these CRANs in neuronal health, lifespan, and
behavioral rhythms. We will use genetic manipulation to determine the causative gene
regulatory events responsible for changes in health and neurodegeneration. The proposed work
should reveal clock-controlled pathways that protect the brain from age-related damage, as well
as examples of age-onset dysregulation of the clock network or connected pathways. Given the
conserved molecular basis of circadian clock and aging biology, we expect these pathways will
also function in humans.
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期刊论文(1)
专著(0)
科研奖励(0)
会议论文
DOI:
10.1038/s41514-022-00092-z
发表时间:
2022-07-27
期刊:
NPJ AGING
影响因子:
--
作者:
[Song, Yujuan, Yang, Jun, Law, Alexander D, Hendrix, David A, Kretzschmar, Doris, Robinson, Matthew, Giebultowicz, Jadwiga M]
通讯作者:
Giebultowicz, Jadwiga M
Integrative transcriptomics to uncover functional elements and disease-associated variants in RNA
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批准号:10707989
-
项目类别:
-
资助金额:$30.56万
-
财政年份:2022
-
负责人:David Anthony Hendrix
-
依托单位:
Uncovering the Gene Regulatory Mechanisms Governing the Aging Circadian Clock
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批准号:9565022
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项目类别:
-
资助金额:$35.99万
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财政年份:2017
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负责人:David Anthony Hendrix
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依托单位:
海外基金