Genetics of Pituitary Development in Zebrafish
斑马鱼垂体发育的遗传学
基本信息
- 批准号:7256095
- 负责人:
- 金额:$ 7.95万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2007
- 资助国家:美国
- 起止时间:2007-04-01 至 2009-03-31
- 项目状态:已结题
- 来源:
- 关键词:AnimalsAwardBreedingCandidate Disease GeneCell TransplantationCellsChimera organismChromosome MappingChromosomes, Human, Pair 5ClassificationCodeComplexConfocal MicroscopyCorticotropinDataDevelopmentEmbryoEmbryonic DevelopmentEssential GenesEthylnitrosoureaFertilizationFishesFoundationsFutureGene MutationGenesGeneticGenetic DeterminismGenetic ScreeningGoalsGreen Fluorescent ProteinsGrowthHormonesHourHumanHypothalamic structureIn SituIn Situ HybridizationLeadLifeMaintenanceMapsMediatingMessenger RNAModelingMolecular GeneticsMutagenesisMutateMutationOligonucleotidesPathway interactionsPatternPhenotypePituitary DiseasesPituitary GlandPituitary HormonesPro-OpiomelanocortinProcessProlactinRNARegulationReverse Transcriptase Polymerase Chain ReactionRoleSignal TransductionSignaling MoleculeSingle-Gene DefectSpecific qualifier valueStagingStudy modelsTestingTimeTissuesTransgenic OrganismsZebrafishbasecell growthdevelopmental geneticsdiencephalonembryo cellin vivoinsightlactotrophmRNA Expressionmutantnovelpositional cloningpromoterresearch studytime usetranscription factortumor
项目摘要
DESCRIPTION (provided by applicant):
Using pituitary pro-opiomelanocortin (POMC) expression as an entry point, the original K08 proposal aims to study genetic and molecular mechanisms underlying corticotroph early ontogeny. Transparent zebrafish embryos expressing green fluorescent protein (GFP) specifically targeted to pituitary corticotroph lineage driven by Pomc gene promoter allows one to follow the dynamic process of pituitary ontogeny in live animals. Ongoing studies in the K08 award isolate mutants using ethylnitrosourea (ENU) mutagenesis of transgenic zebrafish harboring multiple fluorescent tissues including pituitary POMC cells, then classify and categorize these mutants for future systematic studies that aim to identify molecular and genetic mechanisms governing POMC lineage development using gene mapping/cloning and in vivo developmental characterization. Due to known genetic parallels between fish and human, such study will ultimately lead to further insights for human pituitary disease development. This supplemental R03 application focuses on one mutant line generated in pilot ENU mutagenesis screens. Line 1023-5 shows overall normal development at early stages, however, aberrant hypothalamic and pituitary POMC expression pattern at 48 hours post fertilization by whole mount in situ hybridization, thus representing a potentially unique model for studying molecular and genetic regulations of hypothalamic-pituitary/corticotroph axis. Based on preliminary studies, this R03 application will test a single hypothesis: Defective hypothalamic development in mutant 1023-5 (caused by single gene mutation) elicits altered extrinsic signals on pituitary lineage maintenance leading to aberrant POMC cell growth after terminal differentiation. There are two Specific Aims: 1) To identify a single gene defect leading to aberrant POMC phenotype of line 1023-5 using positional cloning; and 2) To characterize hypothalamic and pituitary/corticotroph ontogeny in mutant 1023-5 using RNA whole mount in situ hybridization and in vivo time-lapse confocal microscopy analysis.
Molecular and genetic determinants mediating hypothalamic regulation of corticotroph development are yet to be understood. This study is complimentary to the primary goals of the original K08 proposal. The proposed experiments will validate the experimental approach that will continue with future studies of mutants generated from the K08 award. More importantly, data generated from this study will lead to additional hypotheses enabling development of a R01 application focusing on the function of identified putative gene and associated pathway regulating development of hypothalamus and pituitary.
描述(由申请人提供):
以垂体前阿黑皮素(POMC)表达为切入点,最初的K 08提案旨在研究促肾上腺皮质激素细胞早期个体发育的遗传和分子机制。透明斑马鱼胚胎表达由Pomc基因启动子驱动的特异性靶向垂体促肾上腺皮质激素细胞系的绿色荧光蛋白(GFP),可以观察活体动物垂体个体发育的动态过程。正在进行的研究在K 08奖分离突变体使用乙基亚硝基脲(ENU)诱变的转基因斑马鱼窝藏多个荧光组织,包括垂体POMC细胞,然后分类和归类这些突变体为未来的系统性研究,旨在确定分子和遗传机制POMC谱系发展,使用基因定位/克隆和体内发育表征。由于鱼类和人类之间已知的遗传相似性,这种研究最终将导致对人类垂体疾病发展的进一步了解。该补充R 03申请集中于在中试ENU诱变筛选中产生的一个突变株系。1023-5系胚胎早期发育正常,但在受精后48 h下丘脑和垂体POMC表达异常,为研究下丘脑-垂体/促肾上腺皮质激素轴的分子和遗传调控提供了一个可能的模型。基于初步研究,该R 03申请将测试一个假设:突变体1023-5中的下丘脑发育缺陷(由单基因突变引起)导致垂体谱系维持的外部信号改变,导致终末分化后POMC细胞生长异常。有两个具体目标:1)使用定位克隆鉴定导致品系1023-5的异常POMC表型的单基因缺陷;和2)使用RNA整体原位杂交和体内时间推移共聚焦显微镜分析表征突变体1023-5中的下丘脑和垂体/促肾上腺皮质激素细胞个体发育。
下丘脑调节促肾上腺皮质激素细胞发育的分子和遗传决定因素尚不清楚。本研究是对K 08原始提案主要目标的补充。拟议的实验将验证实验方法,该方法将继续用于K 08奖产生的突变体的未来研究。更重要的是,从这项研究中产生的数据将导致额外的假设,使R 01的应用程序的发展,重点是确定的推定基因的功能和相关的途径调节下丘脑和垂体的发展。
项目成果
期刊论文数量(0)
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{{ truncateString('NING-AI LIU', 18)}}的其他基金
Genetics of Corticotroph Development in Zebrafish
斑马鱼促肾上腺皮质激素发育的遗传学
- 批准号:
7091497 - 财政年份:2003
- 资助金额:
$ 7.95万 - 项目类别:
Genetics of Corticotroph Development in Zebrafish
斑马鱼促肾上腺皮质激素发育的遗传学
- 批准号:
6895208 - 财政年份:2003
- 资助金额:
$ 7.95万 - 项目类别:
Genetics of Corticotroph Development in Zebrafish
斑马鱼促肾上腺皮质激素发育的遗传学
- 批准号:
7256231 - 财政年份:2003
- 资助金额:
$ 7.95万 - 项目类别:
Genetics of Corticotroph Development in Zebrafish
斑马鱼促肾上腺皮质激素发育的遗传学
- 批准号:
6672790 - 财政年份:2003
- 资助金额:
$ 7.95万 - 项目类别:
Genetics of Corticotroph Development in Zebrafish
斑马鱼促肾上腺皮质激素发育的遗传学
- 批准号:
6802301 - 财政年份:2003
- 资助金额:
$ 7.95万 - 项目类别:
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