Transcriptional Activator Complex of the Mammalian Circadian Clock
哺乳动物昼夜节律钟的转录激活剂复合体
基本信息
- 批准号:10379310
- 负责人:
- 金额:$ 45.22万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-06-05 至 2024-03-31
- 项目状态:已结题
- 来源:
- 关键词:ARNTL geneAddressAmino AcidsBehaviorBindingBiochemicalBiologicalBiological ProcessBiological RhythmBipolar DisorderBrainChromatin LoopCircadian RhythmsCollaborationsComplexCryoelectron MicroscopyDNADNA BindingDNA Binding DomainDNA StructureDataDefectDiabetes MellitusDiagnosisDiseaseE-Box ElementsElectron MicroscopyEnhancersFeedbackFeeding behaviorsFunctional disorderGenetic TranscriptionGoalsHealthHealth HazardsHeartHourHumanIncidenceInvestigationKnowledgeLaboratoriesLeadLettersLinkLiverMacromolecular ComplexesMalignant NeoplasmsMammalsMass Spectrum AnalysisMetabolic syndromeMetabolismMethodsMolecularMood DisordersMusMutant Strains MiceNatureNuclearNuclear ExtractObesityPeripheralPhasePhysiologicalPhysiologyPlayPositioning AttributeProcessPropertyProteinsRegulationResolutionRoleSecureSiteSleep DisordersSleep Wake CycleSleep disturbancesStructural ModelsStructureSystemTissuesTranscription CoactivatorTranscriptional Activationcircadiancircadian pacemakerglobal healthimprovedin vivoinsightmonomerparticleprotein complexsleep healthsleep regulationthree dimensional structuretranscription factorvirtual
项目摘要
Project Summary
Circadian clocks are endogenous ~24-hour oscillators that drive daily rhythms of
biological processes. In mammals, circadian clocks are found in the brain and in most
peripheral tissues. Together, the distributed clocks constitute the basic timing system that
regulates physiology, metabolism, and behavior.
The mammalian circadian clock is built on a transcriptional negative feedback loop that
generates circadian rhythms at the molecular level. The transcription factor CLOCK-BMAL1
is at the heart of this feedback loop, acting as the core positive driver of circadian clock
transcription. CLOCK-BMAL1 has been assumed to act in vivo as a heterodimer, but we
have shown that in nuclear extracts from mammalian tissues it is exclusively embedded in an
~800-kDa protein complex during the transcriptional activation phase of the circadian cycle,
far larger than the ~170-kDa heterodimer. Our preliminary biochemical, mass spectrometry,
and single-particle electron microscopy results together unexpectedly suggest that this
complex consists entirely or mostly of multiple CLOCK-BMAL1 heterodimers assembled into
an oligomeric structure.
These observations tell us that the full molecular nature and functional properties of
the circadian clock transcriptional activator remain to be discovered, a fundamental gap in our
understanding. The goal of this application is to analyze the composition, function, and three-
dimensional structure of the enigmatic ~800-kDa CLOCK-BMAL1 complex. If successful, the
project offers to extend and deepen our knowledge of circadian clock transcription, possibly
to an atomic level of resolution.
Advances in understanding the circadian clock will have important implications for our
knowledge of the regulation of behavior and physiology, as well as for human health and
disease. Circadian clock defects result in broad physiological dysfunction, producing
disrupted sleep-wake cycles, metabolic syndrome, and increased cancer incidence. There
are also links between clock dysfunction and mood disorders, including bipolar disorder. The
proposed investigation aims to provide insights into the molecular machinery of the biological
timing system essential for health.
项目摘要
昼夜节律钟是内源性的~24小时振荡器,其驱动生物钟的每日节律。
生物过程。在哺乳动物中,生物钟存在于大脑中,
外周组织分布式时钟共同构成了基本的计时系统,
调节生理代谢和行为
哺乳动物的生物钟建立在转录负反馈环上,
在分子水平上产生昼夜节律。转录因子CLOCK-BMAL 1
是这个反馈回路的核心,是生物钟的核心积极驱动器
转录。人们认为CLOCK-BMAL 1在体内作为异源二聚体发挥作用,但我们
已经表明,在哺乳动物组织的核提取物中,
在昼夜节律周期的转录激活阶段,约800-kDa蛋白复合物,
远大于~170-kDa异二聚体。我们初步的生化分析,质谱分析,
和单粒子电子显微镜的结果出人意料地表明,
复合物完全或大部分由组装成
低聚结构。
这些观察结果告诉我们,
生物钟转录激活因子仍有待发现,这是我们研究中一个基本空白
认识这个应用程序的目标是分析组成,功能,和三个-
神秘的~800-kDa CLOCK-BMAL 1复合物的三维结构。如果成功,则
项目提供了扩展和深化我们的昼夜节律钟转录的知识,可能
达到原子级的分辨率
对生物钟理解的进步将对我们的研究产生重要影响。
行为和生理调节的知识,以及对人类健康和
疾病生物钟缺陷导致广泛的生理功能障碍,
睡眠-觉醒周期紊乱、代谢综合征和癌症发病率增加。那里
也是生物钟功能障碍和情绪障碍,包括双相情感障碍之间的联系。的
拟议的调查旨在提供深入了解生物的分子机制,
定时系统对健康至关重要。
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)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
CHARLES J WEITZ其他文献
CHARLES J WEITZ的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('CHARLES J WEITZ', 18)}}的其他基金
Transcriptional Activator Complex of the Mammalian Circadian Clock
哺乳动物昼夜节律钟的转录激活剂复合体
- 批准号:
10180983 - 财政年份:2020
- 资助金额:
$ 45.22万 - 项目类别:
Transcriptional Activator Complex of the Mammalian Circadian Clock
哺乳动物昼夜节律钟的转录激活剂复合体
- 批准号:
10596126 - 财政年份:2020
- 资助金额:
$ 45.22万 - 项目类别:
Transcriptional Activator Complex of the Mammalian Circadian Clock
哺乳动物昼夜节律钟的转录激活剂复合体
- 批准号:
9884255 - 财政年份:2020
- 资助金额:
$ 45.22万 - 项目类别:
Mammalian circadian clock: genetics of PERIOD complex composition and structure.
哺乳动物生物钟:周期复杂组成和结构的遗传学。
- 批准号:
9336364 - 财政年份:2016
- 资助金额:
$ 45.22万 - 项目类别:
相似海外基金
Rational design of rapidly translatable, highly antigenic and novel recombinant immunogens to address deficiencies of current snakebite treatments
合理设计可快速翻译、高抗原性和新型重组免疫原,以解决当前蛇咬伤治疗的缺陷
- 批准号:
MR/S03398X/2 - 财政年份:2024
- 资助金额:
$ 45.22万 - 项目类别:
Fellowship
Re-thinking drug nanocrystals as highly loaded vectors to address key unmet therapeutic challenges
重新思考药物纳米晶体作为高负载载体以解决关键的未满足的治疗挑战
- 批准号:
EP/Y001486/1 - 财政年份:2024
- 资助金额:
$ 45.22万 - 项目类别:
Research Grant
CAREER: FEAST (Food Ecosystems And circularity for Sustainable Transformation) framework to address Hidden Hunger
职业:FEAST(食品生态系统和可持续转型循环)框架解决隐性饥饿
- 批准号:
2338423 - 财政年份:2024
- 资助金额:
$ 45.22万 - 项目类别:
Continuing Grant
Metrology to address ion suppression in multimodal mass spectrometry imaging with application in oncology
计量学解决多模态质谱成像中的离子抑制问题及其在肿瘤学中的应用
- 批准号:
MR/X03657X/1 - 财政年份:2024
- 资助金额:
$ 45.22万 - 项目类别:
Fellowship
CRII: SHF: A Novel Address Translation Architecture for Virtualized Clouds
CRII:SHF:一种用于虚拟化云的新型地址转换架构
- 批准号:
2348066 - 财政年份:2024
- 资助金额:
$ 45.22万 - 项目类别:
Standard Grant
BIORETS: Convergence Research Experiences for Teachers in Synthetic and Systems Biology to Address Challenges in Food, Health, Energy, and Environment
BIORETS:合成和系统生物学教师的融合研究经验,以应对食品、健康、能源和环境方面的挑战
- 批准号:
2341402 - 财政年份:2024
- 资助金额:
$ 45.22万 - 项目类别:
Standard Grant
The Abundance Project: Enhancing Cultural & Green Inclusion in Social Prescribing in Southwest London to Address Ethnic Inequalities in Mental Health
丰富项目:增强文化
- 批准号:
AH/Z505481/1 - 财政年份:2024
- 资助金额:
$ 45.22万 - 项目类别:
Research Grant
ERAMET - Ecosystem for rapid adoption of modelling and simulation METhods to address regulatory needs in the development of orphan and paediatric medicines
ERAMET - 快速采用建模和模拟方法的生态系统,以满足孤儿药和儿科药物开发中的监管需求
- 批准号:
10107647 - 财政年份:2024
- 资助金额:
$ 45.22万 - 项目类别:
EU-Funded
Ecosystem for rapid adoption of modelling and simulation METhods to address regulatory needs in the development of orphan and paediatric medicines
快速采用建模和模拟方法的生态系统,以满足孤儿药和儿科药物开发中的监管需求
- 批准号:
10106221 - 财政年份:2024
- 资助金额:
$ 45.22万 - 项目类别:
EU-Funded
Recite: Building Research by Communities to Address Inequities through Expression
背诵:社区开展研究,通过表达解决不平等问题
- 批准号:
AH/Z505341/1 - 财政年份:2024
- 资助金额:
$ 45.22万 - 项目类别:
Research Grant