The Vertebrate Translocon Sec61alpha is Required for Habenular Asymmetry
脊椎动物 Translocon Sec61alpha 是缰核不对称所必需的
基本信息
- 批准号:8038286
- 负责人:
- 金额:$ 2.58万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2010
- 资助国家:美国
- 起止时间:2010-03-01 至 2013-02-28
- 项目状态:已结题
- 来源:
- 关键词:AblationAnimal ModelArchitectureAreaAutistic DisorderBehaviorBrainBroca&aposs areaBromodeoxyuridineCell CycleCellsCodeComplexConchaCrowsDataDate of birthDevelopmentDisciplineDorsalDyslexiaEctopic ExpressionEmbryoEmotionsEndoplasmic ReticulumEnvironmentEpithalamic structureFamilyGene ExpressionGenesGeneticHabenulaHabenular NucleusHandHomologous GeneHumanImageIn Situ HybridizationIndividualLanguageLasersLateralLeftMedialMediatingMicroscopyMindMitosisMonitorMorphologyMovementMusMutationNervous system structureNeuronsPathway interactionsPatternPeptidesPositioning AttributeProtein translocationProteinsRNARNA analysisRegulationResearchRight-OnRoleSchizophreniaSideSignal TransductionStem cellsStructureTechniquesTimeTissuesTransgenic OrganismsTranslatingUncertaintyWorkZebrafishcell behaviorcell motilitydevelopmental geneticsdiencephalongene conservationloss of functionmigrationmind controlmutantneurogenesisnotch proteinoverexpressionpreventprogenitorpublic health relevancestem
项目摘要
DESCRIPTION (provided by applicant): The scientific approach to the human brain has always been limited by the sheer number of neurons: estimated at 10 billion to 1 trillion neurons (Williams and Herrup 1998). Cross sections through a human brain reveal carefully segregated centers that can regulate precise bodily functions or complex emotions. A comparison between the hemispheres uncovers many L/R differences. For example, Broca's area, an area which codes for language, is larger on the left side of most right-handed, normally developed individuals (Fossi et al 2004). Asymmetry is not unique to the human brain: lateralized differences in brain architecture, gene expression, and function can be witnessed across the vertebrate clade (Concha and Wilson 2001). We have implicated a secretory pathway gene as a contributing factor to developing asymmetry in the zebrafish. This gene,)sec6111, is the major subunit of the vertebrate translocon, a pore on the endoplasmic reticulum which accepts newly translated peptides into the secretory pathway (Rapoport 2007). We doubt that the pore itself has neurogenic capacity; it likely regulates early components of the asymmetry pathway.) Developmental genetics represents one reductionist discipline with potential to help decode the mysteries of the vertebrate nervous system. Utilizing a model organism such as the zebrafish, we can monitor asymmetric brain development in a less intricate environment, yet retain high conservation of gene identity to human homologs. The zebrafish is amenable to both gain and loss of function techniques, and has powerful transgenic monitoring capacity. This allows us to visualize early cell behaviors, connections, and movements that contribute to early brain development, with careful reference to the contributions of individual genes. In my research, I plan to examine several possible mechanisms by which the sec6111 gene impacts habenular neurogenesis in the zebrafish. I will first examine the effects of the translocon on habenular subnuclear neurogenesis, which can be distinguished through in situ hybridization for specific marker genes, birth-date analysis through BrdU incorporation, and time-lapse microscopy of progenitor cell migration from the ventral epithalamus. Next, I will focus on the epithalamic roof plate, a crucial signaling center in the developing nervous system. We believe the roof plate influences habenular progenitor migration, and that the Notch signaling family may regulate roof plate formation. in situ hybridization for roof plate markers and laser ablation of the roof plate with illuminate the impact of this dorsal structure in both sec6111 and Notch pathway mutants, as compared to wild type. Finally, we will investigate whether sec6111 acts in the habenular progenitors or in the roof plate, through genetic mosaic analysis, RNA rescue, and habenular-specific expression of the gene.
PUBLIC HEALTH RELEVANCE: The left and right hemispheres of the human brain are not created equal: some regions of the brain control behaviors unilaterally. These L/R differences include specialized functions, such as the left hemisphere-specific coding of language (De Fossi et al 2004), and it has been suggested that asymmetry is disrupted in schizophrenia (Mitchell and Crow 2005), autism (De Fossi et al 2004), and dyslexia (Leonard and Eckert 2008). By characterizing the highly conserved genes that contribute to the development of asymmetry in zebrafish, we can extrapolate to their human counterparts for a better understanding of how and why asymmetry is generated in the brain.
描述(由申请人提供):人类大脑的科学方法一直受到神经元数量的限制:估计为100亿至1万亿个神经元(威廉姆斯和Herrup 1998)。人类大脑的横截面揭示了仔细分离的中心,这些中心可以调节精确的身体功能或复杂的情绪。两个半球之间的比较揭示了许多L/R差异。例如,布罗卡区,一个编码语言的区域,在大多数右撇子的左侧较大,正常发育的个体(Fossi et al 2004)。不对称性并不是人类大脑所独有的:大脑结构、基因表达和功能的侧化差异可以在脊椎动物的进化枝中看到(Concha and Wilson 2001)。 我们有牵连的分泌途径基因作为一个促成因素,发展不对称的斑马鱼。该基因(sec 6111)是脊椎动物易位子的主要亚基,易位子是内质网上的孔,其接受新翻译的肽进入分泌途径(Rapoport 2007)。我们怀疑孔本身具有神经原性能力;它可能调节不对称通路的早期成分。) 发育遗传学代表了一个还原论的学科,有可能帮助解码脊椎动物神经系统的奥秘。利用模式生物,如斑马鱼,我们可以监测不对称的大脑发育在一个不太复杂的环境中,但保持高度保守的基因身份的人类同源物。斑马鱼是一种既可用于功能获得又可用于功能丧失的动物,具有很强的转基因监测能力。这使我们能够可视化有助于早期大脑发育的早期细胞行为、连接和运动,并仔细参考单个基因的贡献。 在我的研究中,我计划研究sec 6111基因影响斑马鱼缰神经发生的几种可能机制。我将首先检查的影响,translocon缰核亚神经发生,这可以通过特定的标记基因,出生日期分析,通过BrdU掺入,和延时显微镜的祖细胞迁移从腹侧上丘脑的原位杂交区分。接下来,我将重点介绍上丘脑顶板,这是发育中的神经系统中至关重要的信号中心。我们认为顶板影响缰祖细胞迁移,Notch信号家族可能调节顶板的形成。与野生型相比,顶板标记物的原位杂交和顶板的激光消融阐明了sec 6111和Notch途径突变体中该背侧结构的影响。最后,我们将调查是否sec 6111行为的缰祖细胞或顶板,通过遗传镶嵌分析,RNA拯救,和缰特异性表达的基因。
公共卫生关系:人类大脑的左半球和右半球并不是生来平等的:大脑的某些区域单方面控制行为。这些L/R差异包括特殊功能,例如左半球特异性语言编码(De Fossi et al 2004),并且已经表明不对称性在精神分裂症(Mitchell and Crow 2005)、自闭症(De Fossi et al 2004)和阅读障碍(伦纳德and Eckert 2008)中被破坏。通过表征有助于斑马鱼不对称发展的高度保守基因,我们可以推断它们的人类同行,以更好地了解大脑中如何以及为什么产生不对称。
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 }}
Caleb Andrew Doll其他文献
Caleb Andrew Doll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('Caleb Andrew Doll', 18)}}的其他基金
The RNA Binding Protein FMRP Promotes Myelin Sheath Growth
RNA 结合蛋白 FMRP 促进髓鞘生长
- 批准号:
10039005 - 财政年份:2020
- 资助金额:
$ 2.58万 - 项目类别:
The Vertebrate Translocon Sec61alpha is Required for Habenular Asymmetry
脊椎动物 Translocon Sec61alpha 是缰核不对称所必需的
- 批准号:
8231547 - 财政年份:2010
- 资助金额:
$ 2.58万 - 项目类别:
The Vertebrate Translocon Sec61alpha is Required for Habenular Asymmetry
脊椎动物 Translocon Sec61alpha 是缰核不对称所必需的
- 批准号:
7913747 - 财政年份:2010
- 资助金额:
$ 2.58万 - 项目类别:
相似海外基金
Quantification of Neurovasculature Changes in a Post-Hemorrhagic Stroke Animal-Model
出血性中风后动物模型中神经血管变化的量化
- 批准号:
495434 - 财政年份:2023
- 资助金额:
$ 2.58万 - 项目类别:
Small animal model for evaluating the impacts of cleft lip repairing scar on craniofacial growth and development
评价唇裂修复疤痕对颅面生长发育影响的小动物模型
- 批准号:
10642519 - 财政年份:2023
- 资助金额:
$ 2.58万 - 项目类别:
Bioactive Injectable Cell Scaffold for Meniscus Injury Repair in a Large Animal Model
用于大型动物模型半月板损伤修复的生物活性可注射细胞支架
- 批准号:
10586596 - 财政年份:2023
- 资助金额:
$ 2.58万 - 项目类别:
A Comparison of Treatment Strategies for Recovery of Swallow and Swallow-Respiratory Coupling Following a Prolonged Liquid Diet in a Young Animal Model
幼年动物模型中长期流质饮食后吞咽恢复和吞咽呼吸耦合治疗策略的比较
- 批准号:
10590479 - 财政年份:2023
- 资助金额:
$ 2.58万 - 项目类别:
Diurnal grass rats as a novel animal model of seasonal affective disorder
昼夜草鼠作为季节性情感障碍的新型动物模型
- 批准号:
23K06011 - 财政年份:2023
- 资助金额:
$ 2.58万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Longitudinal Ocular Changes in Naturally Occurring Glaucoma Animal Model
自然发生的青光眼动物模型的纵向眼部变化
- 批准号:
10682117 - 财政年份:2023
- 资助金额:
$ 2.58万 - 项目类别:
A whole animal model for investigation of ingested nanoplastic mixtures and effects on genomic integrity and health
用于研究摄入的纳米塑料混合物及其对基因组完整性和健康影响的整体动物模型
- 批准号:
10708517 - 财政年份:2023
- 资助金额:
$ 2.58万 - 项目类别:
A Novel Large Animal Model for Studying the Developmental Potential and Function of LGR5 Stem Cells in Vivo and in Vitro
用于研究 LGR5 干细胞体内外发育潜力和功能的新型大型动物模型
- 批准号:
10575566 - 财政年份:2023
- 资助金额:
$ 2.58万 - 项目类别:
Elucidating the pathogenesis of a novel animal model mimicking chronic entrapment neuropathy
阐明模拟慢性卡压性神经病的新型动物模型的发病机制
- 批准号:
23K15696 - 财政年份:2023
- 资助金额:
$ 2.58万 - 项目类别:
Grant-in-Aid for Early-Career Scientists
The effect of anti-oxidant on swallowing function in an animal model of dysphagia
抗氧化剂对吞咽困难动物模型吞咽功能的影响
- 批准号:
23K15867 - 财政年份:2023
- 资助金额:
$ 2.58万 - 项目类别:
Grant-in-Aid for Early-Career Scientists