Developmental regulation of oscillatory expression
振荡表达的发育调节
基本信息
- 批准号:9322167
- 负责人:
- 金额:$ 1.38万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2015
- 资助国家:美国
- 起止时间:2015-09-18 至 2019-05-31
- 项目状态:已结题
- 来源:
- 关键词:ArabidopsisAutomobile DrivingBerylliumBindingBiologicalBiological AssayBiological PacemakersCellsCellular biologyComplexDevelopmentDevelopmental BiologyElementsEmbryoFeedbackFrequenciesGamma RaysGenetic TranscriptionGoalsHandHealthHistocompatibility TestingHourIndiumIndividualLateralLifeMalignant Childhood NeoplasmMesodermMesoderm CellMetabolicMethodsModelingMolecularMoltingNuclearPatternPhysiologic pulsePlant RootsPost-Transcriptional RegulationProcessProteinsRNARegulationRegulatory ElementReporterResolutionRhabdomyosarcomaRibonucleoproteinsSegmentation Clock PathwaySignal PathwaySignal TransductionSomitesStarvationSystemTP53 geneTherapeuticTissue EngineeringTrans-ActivatorsTranscriptTranscription Repressor/CorepressorTranscriptional RegulationUntranslated RegionsUp-RegulationVertebratesWorkYeastsZebrafishbiological systemscancer cellcell typecytokineembryonic stem cellhuman diseaseimprovedin vivonerve stem cellresponsesomitogenesisstem cell biologytranscription factor
项目摘要
DESCRIPTION (provided by applicant): The vertebrate segmentation clock is a model biological oscillator that generates periodic pattern in developing embryos. The segmentation clock controls somitogenesis, the process by which the mesoderm of the vertebrate animal is sequentially divided into segmental units called somites. At the core of the segmentation clock is an auto-inhibitory negative feedback loop involving her/Hes transcriptional repressors. Although the `clock and wave front' model of somitogenesis is widely accepted, there are still many aspects of clock regulation that are not understood, and yet other aspects that may be challenged as our ability to examine oscillation dynamics in vivo becomes more sophisticated. It is only over the last few years that we have been able to watch the segmentation clock oscillate in living embryos and only very recently that have we been able to do so with single cell resolution. As our ability to detect rapid biological oscillations improves, more and more examples of biological oscillators controlling diverse cellular responses and cell fate decisions are being discovered, underscoring a critical need to understand how they are regulated. In this proposal, we will focus on characterizing the cis regulatory elements and trans-acting factors required for a largely understudied but critical aspect of oscillatory systems - that of cyclic transcript decay. Rapid transcript turnover is critical in oscillatory systems like the vertebrate segmentation clock, where every round of transcription must be followed by a wave of transcript decay to sustain oscillations. We already have one factor in hand, Pnrc2, which will greatly facilitate the identification of a cyclic transcript "decay complex". We anticipate that this work ill broadly impact our understanding of regulation of RNA turnover in many developmental contexts. Rapid molecular oscillators are not only important for generating segmental pattern during development, but also for promoting heterogeneous responses in neural stem cells, and for biasing embryonic stem cells toward different cell fates. Additionally, Hes1 upregulation promotes rhabdomyosarcoma, an aggressive childhood cancer. Thus, the more we understand cyclic regulation, the more likely we are to develop promising treatments or therapeutics for human disease. We propose to uncover regulatory mechanisms, elements, and factors that control oscillation dynamics in one such oscillatory system, the vertebrate segmentation clock, and anticipate that our work will impact studies in fields as diverse as developmental biology, stem cell biology, tissue engineering, and possibly cancer cell biology.
描述(由申请人提供):脊椎动物分段时钟是一种模型生物振荡器,可在发育中的胚胎中产生周期性模式。分节时钟控制体节发生,即脊椎动物的中胚层依次分为称为体节的节段单位的过程。分段时钟的核心是涉及她/他转录抑制子的自抑制负反馈环。尽管体细胞发生的“时钟和波前”模型已被广泛接受,但时钟调节的许多方面仍有待了解,而且随着我们检查体内振荡动力学的能力变得更加复杂,其他方面可能会受到挑战。直到最近几年,我们才能够观察活体胚胎中的分割时钟振荡,直到最近我们才能够以单细胞分辨率做到这一点。随着我们检测快速生物振荡的能力不断提高,越来越多的生物振荡器控制不同细胞反应和细胞命运决定的例子被发现,这凸显了了解它们如何调节的迫切需要。 在本提案中,我们将重点描述振荡系统的一个很大程度上未被充分研究但至关重要的方面(循环转录物衰减)所需的顺式调控元件和反式作用因子。快速转录本周转对于像脊椎动物分节时钟这样的振荡系统至关重要,其中每轮转录都必须跟随一波转录本衰减以维持振荡。我们手上已经有了一个因子,Pnrc2,它将极大地促进循环转录本“衰变复合体”的识别。我们预计这项工作将广泛影响我们对许多发育环境中 RNA 周转调节的理解。 快速分子振荡器不仅对于在发育过程中生成节段模式很重要,而且对于促进神经干细胞的异质反应以及使胚胎干细胞偏向不同的细胞命运也很重要。此外,Hes1 上调会促进横纹肌肉瘤(一种侵袭性儿童癌症)。因此,我们对循环调节了解得越多,我们就越有可能开发出有前景的人类疾病治疗方法。我们建议揭示控制这样一个振荡系统(脊椎动物分节时钟)中振荡动力学的调控机制、元素和因素,并预计我们的工作将影响发育生物学、干细胞生物学、组织工程以及可能的癌细胞生物学等多个领域的研究。
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)
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Sharon L Amacher其他文献
Sharon L Amacher的其他文献
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{{ truncateString('Sharon L Amacher', 18)}}的其他基金
Survival Motor Neuron (SMN) function in motoneuron development
运动神经元存活 (SMN) 在运动神经元发育中的功能
- 批准号:
9899326 - 财政年份:2017
- 资助金额:
$ 1.38万 - 项目类别:
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