Genetics of Corticotroph Development in Zebrafish

描述（由申请人提供）： 在脊椎动物发育过程中，促肾上腺皮质激素细胞的个体发生涉及与其他垂体细胞谱系不同的分子途径。促肾上腺皮质激素细胞分化的关键决定因素仍不清楚。转录因子和可溶性分子通过Jak/STAT途径信号转导参与促肾上腺皮质激素细胞的发育和前阿黑皮素（POMC）的表达。以POMC的表达为切入点，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。本K 08提案的目的是（1）阐明STAT 3在POMC谱系发育中的关键作用;（2）进行遗传筛选以鉴定和表征POMC谱系发育所需的必需基因。后一个目标将通过参与NIH资助的器官特异性遗传筛选来实现，该筛选利用携带荧光组织的活转基因斑马鱼。表达由POMC启动子驱动的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，允许对活胚胎中的POMC特异性细胞进行详细的遗传分析。 作为这一建议的候选人，我目前是加州大学洛杉矶分校雪松-西奈医学中心（CSMC）内分泌科的研究员，并将于2003年6月完成我的奖学金。通过拟议的研究，我将扩大我在普通和神经内分泌学，特别是垂体发育生物学方面的知识，并进一步接受分子生物学、遗传学、胚胎学和内分泌学方面的广泛培训。在这个奖项结束时，我将受到出色的训练，在垂体发育方面进行独立的基础研究，并在学术医学领域从事富有成效的研究事业。 CSMC和UCLA的教师在强大的基础研究和培训医生以发展学术医学的独立职业方面享有盛誉。我将由CSMC和UCLA的内分泌和发育生物学教师指导，这将为K 08应用提供协同富集。CSMC拥有与我的建议和研究兴趣相关的完善计划，并完全致力于在学术卓越的环境中维持我的研究职业发展。

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.