Regulation and function of subcellular RNA localization in neural crest cells and their derivatives
神经嵴细胞及其衍生物亚细胞RNA定位的调控和功能
基本信息
- 批准号:10739280
- 负责人:
- 金额:$ 13.24万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-07-20 至 2025-06-30
- 项目状态:未结题
- 来源:
- 关键词:AddressAdvisory CommitteesAffectAttentionAwardBiological AssayCatalogsCell physiologyCellsCo-ImmunoprecipitationsCongenital AbnormalityDataDefectDevelopmentDiagnosisDiseaseElementsEmbryonic DevelopmentEnvironmentGaliumGenesGenetic EngineeringGenetic TranscriptionGoalsHeadHumanImage AnalysisIn VitroIndividualInterventionInvadedKinesinLearningLinkLocationMalignant NeoplasmsMammalian CellMelanoma CellMentorshipMessenger RNAModelingMolecularMotorMusMutationNeural CrestNeural Crest CellNeurologicNeuronsOutcomePathway interactionsPhenotypePhysiologicalPhysiologyPost-Transcriptional RegulationPreventionProcessProteinsRNARegulationResearchResourcesRoleRouteRunningSchwann CellsSystemTechniquesTechnologyTestingTimeTissuesTotal Internal Reflection FluorescentTrainingTrans-ActivatorsTranscription ProcessTranslationscancer geneticscareercell behaviorcell motilitycell typecollaborative environmentcraniofacialdesignexperienceexperimental studyfallsgain of function mutationin vivoinsightinterestlight microscopyloss of functionmelanocytemelanomamigrationmouse modelnovelposttranscriptionalprogramsprotein functionprotein protein interactionsingle moleculetraffickingtranscriptomicstumor progression
项目摘要
PROJECT SUMMARY
The long-term objective of this project is to determine the general principles and causal mechanisms
underlying subcellular RNA localization, and the physiological implications during development and disease. In
particular, the subcellular localization of messenger RNA (mRNA) to cell protrusions is known to be required
for cell migration, but the mechanisms by which mRNA localization regulates protein function in this setting are
unclear. Many genes implicated in mRNA localization are expressed in neural crest cells, which are
a particularly migratory cell type that gives rise to much of the vertebrate head, as well as neurons,
melanocytes, and aggressive cancers including melanoma. As such, neural crest cells provide a rich
environment to uncover molecular mechanisms of mRNA localization in cell migration as well as the relevance
there of to mammalian physiology. In this project, I will use cultured melanoma cells to identify and
characterize trans-acting regulators of mRNA localization and elucidate the role of mRNA localization on
protein function. I will also use in vivo mouse models to catalog mRNA localization that occurs during neural
crest cell development and directly test the role of a well characterized localized mRNA, Kif1c, during
development and cancer onset and progression. As neural crest and cancer genetics fields rely heavily on
transcriptional studies, the mechanistic understanding of a post-transcriptional process as described here may
provide unique insight into the cause, diagnosis and treatment of craniofacial birth defects and melanoma
onset and progression.
My career goal is to run an academic research program analyzing the role and regulation of subcellular RNA
localization during embryogenesis, with special attention to neural crest cells and their derivatives. My ambition
is to have a lab that can determine molecular mechanisms at the single-molecule level and causally link those
processes to physiological outcomes in vivo. To this end, the proposed experiments and training plan are
designed to develop expertise in cutting-edge technologies such as TIRF microscopy, computational image
analysis, genetic engineering and in vivo disease assays. Training in these advanced techniques will be
directly supported by the resource-rich and collaborative environment at UT Southwestern, and especially
mentorship from Dr. Gaudenz Danuser, Dr. Ondine Cleaver, Dr. Khuloud Jaqaman, Dr. Lu Le and Dr. Sean
Morrison, who make up my advisory committee. The Pathway to Independence Award will provide the time,
resources and autonomy to fully develop and initiate this ambitious research program and accrue the
resources, expertise and experience necessary to launch an impactful, thriving research lab in Fall 2024.
项目摘要
本项目的长期目标是确定一般原则和因果机制
潜在的亚细胞RNA定位,以及发育和疾病过程中的生理意义。在
特别地,已知需要信使RNA(mRNA)到细胞突起的亚细胞定位
细胞迁移,但在这种情况下,mRNA定位调节蛋白质功能的机制是
不清楚许多与mRNA定位有关的基因在神经嵴细胞中表达,
一种特殊的迁移细胞类型,它产生了脊椎动物头部的大部分,以及神经元,
黑素细胞和包括黑色素瘤在内的侵袭性癌症。因此,神经嵴细胞提供了丰富的
环境,以揭示细胞迁移中mRNA定位的分子机制以及
对哺乳动物生理学的影响。在这个项目中,我将使用培养的黑色素瘤细胞来识别和
表征mRNA定位的反式作用调节因子,并阐明mRNA定位在
蛋白质功能我还将使用体内小鼠模型来分类神经细胞生长过程中发生的mRNA定位,
嵴细胞发育,并直接测试一个良好的特点定位mRNA,Kif1c的作用,在
发展和癌症发作和进展。由于神经嵴和癌症遗传学领域严重依赖
转录研究,如这里所描述的转录后过程的机制理解可以
提供独特的见解的原因,诊断和治疗颅面出生缺陷和黑色素瘤
发病和进展。
我的职业目标是运行一个学术研究项目,分析亚细胞RNA的作用和调节
在胚胎发生过程中的定位,特别注意神经嵴细胞及其衍生物。我的志向
就是有一个实验室可以在单分子水平上确定分子机制,
过程到体内生理结果。为此,建议的实验和培训计划是
旨在发展尖端技术的专业知识,如TIRF显微镜,计算图像
分析、基因工程和体内疾病测定。这些先进技术的培训将是
直接由UT西南资源丰富和协作环境的支持,特别是
来自Gaudenz Danuser博士、Ondine Cleaver博士、Khuloud Jaqaman博士、Lu Le博士和Sean博士的指导
莫里森,他们组成了我的顾问委员会。独立之路奖将提供时间,
资源和自主权,充分开发和启动这一雄心勃勃的研究计划,并积累
在2024年秋季推出一个有影响力的,蓬勃发展的研究实验室所需的资源,专业知识和经验。
项目成果
期刊论文数量(0)
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专利数量(0)
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Megan L Norris其他文献
Localization of Kif1c mRNA to cell protrusions dictates binding partner specificity of the encoded protein
Kif1c mRNA 对细胞突起的定位决定了所编码蛋白质的结合伴侣特异性
- DOI:
10.1101/2022.11.07.515531 - 发表时间:
2022 - 期刊:
- 影响因子:0
- 作者:
Megan L Norris;J. Mendell - 通讯作者:
J. Mendell
Megan L Norris的其他文献
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{{ truncateString('Megan L Norris', 18)}}的其他基金
Toddler and Apelin Signaling During Zebrafish Gastrulation
斑马鱼原肠胚形成过程中的幼儿和 Apelin 信号传导
- 批准号:
8784314 - 财政年份:2014
- 资助金额:
$ 13.24万 - 项目类别:
Toddler and Apelin Signaling During Zebrafish Gastrulation
斑马鱼原肠胚形成过程中的幼儿和 Apelin 信号传导
- 批准号:
9116889 - 财政年份:2014
- 资助金额:
$ 13.24万 - 项目类别:
Toddler and Apelin Signaling During Zebrafish Gastrulation
斑马鱼原肠胚形成过程中的幼儿和 Apelin 信号传导
- 批准号:
8966556 - 财政年份:2014
- 资助金额:
$ 13.24万 - 项目类别:
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