Stage-specific responses to steroid hormones

描述（由申请人提供）：对核激素受体的广泛研究已经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程序的新见解。然而，尽管取得了这些重大进展，仍然存在一些重要问题。其中的核心是如何在激素信号传导中实现时间特异性。相同激素的重复脉冲如何在不同时间引导不同的遗传和生物反应？我建议解决这个问题，使用果蝇作为一个模型系统，专注于prepupal能力因子和孤儿核受体betaFTZ-F1在提供时间特异性的类固醇激素蜕皮激素的脉冲在变态过程中的作用。我将使用微阵列从蜕皮激素处理的野生型动物器官培养物以及功能获得和功能丧失的betaFTZ-F1突变体中获得全基因组表达谱。这些研究将导致识别蜕皮激素以阶段特异性方式调节的基因，仅响应于蛹前蜕皮激素脉冲并依赖于β FTZ-F1感受态因子。这些基因中的几个将被选择用于详细的功能分析，以确定它们在发育的这个阶段的生物学作用。这里提出的研究将提供新的见解类固醇反应能力的分子机制，以及了解如何在激素信号通路的时间特异性实现的基础。

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.