Stage-specific responses to steroid hormones

描述(申请人提供)：对核激素受体的广泛研究改变了分子内分泌学领域，导致对这些配体调节的转录因子如何控制广泛的生物学程序有了新的见解。然而，尽管取得了这些重大进展，一些重要问题仍然存在。其中的核心是如何在激素信号中实现时间特异性。同一种激素的重复脉冲如何在不同的时间引导不同的遗传和生物反应？我建议通过以果蝇为模型系统来解决这个问题，重点研究预蛹能力因子和孤儿核受体βFTZ-F1在变态过程中为类固醇激素蜕皮激素脉冲提供时间特异性的作用。我将使用微阵列从野生型动物经蜕皮激素处理的器官培养物以及功能获得和功能丧失的BetaFTZ-F1突变体获得全基因组表达谱。这些研究将导致识别以特定阶段的方式受蜕皮激素调控的基因，仅对预蛹蜕皮激素脉冲作出反应，并依赖于βFTZ-F1能力因子。这些基因中的几个将被选择进行详细的功能分析，以确定它们在发育阶段的生物学作用。这些研究将为类固醇反应的分子机制提供新的见解，并为理解激素信号通路中的时间特异性是如何实现的奠定了基础。

DESCRIPTION (provided by applicant): Extensive studies of nuclear hormone receptors have transformed the field of molecular endocrinology, leading to new insights into how these ligand-regulated transcription factors control a broad range of biological programs. In spite of these significant advances, however, a number of important questions remain. Central among these is how temporal specificity is achieved in hormone signaling. How do repeated pulses of the same hormone direct different genetic and biological responses at different times? I propose to address this question by using Drosophila as a model system, focusing on the role of the prepupal competence factor and orphan nuclear receptor betaFTZ-F1 in providing temporal specificity to pulses of the steroid hormone ecdysone during metamorphosis. I will use microarrays to obtain genome wide expression profiles from ecdysone-treated organ cultures of wild-type animals and from both gain-of-function and loss-of-function betaFTZ-F1 mutants. These studies will lead to the identification of genes that are regulated by ecdysone in a stage-specific manner, responding to only the prepupal ecdysone pulse and dependent on the betaFTZ-F1 competence factor. Several of these genes will be selected for detailed functional analysis to determine their biological roles at this stage in development. The studies proposed here will provide new insights into the molecular mechanisms of competence for steroid responses as well as a basis for understanding how temporal specificity is achieved in hormone signaling pathways.