Genetics of Corticotroph Development in Zebrafish

描述(由申请人提供)： 脊椎动物发育过程中促肾上腺皮质激素个体发育涉及不同于其他脑垂体细胞系的分子途径。促肾上腺皮质细胞分化的关键决定因素在很大程度上仍不清楚。转录因子和可溶性分子通过Jak/STAT信号通路参与促肾上腺皮质激素的发育和前阿片黑素皮质素(POMC)的表达。以POMC表达为切入点，我建议研究斑马鱼促肾上腺皮质激素决定和分化的遗传和分子机制。这个K08提案的目的是(1)阐明STAT3在POMC谱系发育中的关键作用；(2)进行遗传筛选，以确定和表征POMC谱系发育所需的必要基因。后一个目标将通过参与美国国立卫生研究院资助的器官特异性基因筛查来实现，该筛查利用含有荧光组织的活转基因斑马鱼。由POMC启动子驱动表达绿色荧光蛋白的转基因斑马鱼提供了一种独特的体内模型，可以对活胚胎中POMC特异的细胞进行详细的遗传分析。 作为这项提案的候选人，我目前是加州大学洛杉矶分校锡达斯-西奈医学中心(CSMC)内分泌科的研究员，将于2003年6月完成我的研究员资格。通过拟议的研究，我将扩大我对普通和神经内分泌学的知识，特别是脑垂体发育生物学，并进一步在分子生物学、遗传学、胚胎学和内分泌学方面进行广泛的培训。到这个奖项结束时，我将接受卓越的培训，从事脑下垂体发育的独立基础研究，并在学术医学方面追求富有成效的研究生涯。 CSMC和加州大学洛杉矶分校的教职员工在强大的基础研究和培训医生在学术医学领域发展独立职业方面都享有极高的声誉。我将得到CSMC和加州大学洛杉矶分校内分泌和发育生物学系的指导，这将为K08的应用提供协同丰富。CSMC拥有与我的建议和研究兴趣相关的成熟项目，并完全致力于在学术卓越的环境下支持我的研究事业发展。

DESCRIPTION (provided by applicant): Corticotroph ontogeny during vertebrate development involves molecular pathways distinct from other pituitary cell lineages. The critical determinants of corticotroph differentiation remain largely unclear. Both transcription factors and soluble molecules signaling via Jak/STAT pathways are involved in corticotroph development and pro-opiomelanocortin (POMC) expression. Using POMC expression as an entry point, I propose to study genetic and molecular mechanisms underlying corticotroph determination and differentiation in zebrafish. The aims of this K08 proposal are (1) to elucidate the critical roles of STAT 3 in POMC lineage development; (2) to perform a genetic screen to identify and characterize essential genes required for development of POMC lineage. The latter aim will be achieved through participation in a NIH-funded organ-specific genetic screen that utilizes live transgenic zebrafish harboring fluorescent tissues. Transgenic zebrafish expressing green fluorescent protein driven by the POMC promoter offer a unique in vivo model allowing a detailed genetic analysis of POMC-specific cells in living embryos. As the candidate for this proposal, I am currently a fellow in the Division of Endocrinology, Cedars- Sinai Medical Center (CSMC), UCLA and will complete my fellowship in June 2003. Through the proposed studies, I will expand my knowledge of general and neuro- endocrinology, especially pituitary developmental biology, and further a broad training in molecular biology, genetics, embryology and endocrinology. By the end of this award, I will be eminently trained to undertake independent basic research in pituitary development and to pursue a productive research career in academic medicine. The faculty at CSMC and UCLA have excellent reputations in both strong basic research and training physicians to develop independent careers in academic medicine. I will be mentored by both endocrine and developmental biology faculty at CSMC and UCLA, which will provide synergistic enrichment for this K08 application. CSMC has well-established programs related to my proposal and research interests and is fully committed to sustain my research career development in an environment of academic excellence.