Role of a Novel Corepressor in Nuclear Receptor Action

描述(申请人提供)：这项工作的长期目标是了解荷尔蒙控制的基因调控网络如何调控发育和生理过程。核受体通过激活特定基因的表达来调节多种激素的作用。一些核受体也可以通过与辅阻遏子结合来抑制转录，但对抑制的机制和意义知之甚少。本研究的重点是一种新的核受体辅阻遏子，它是由哺乳动物无毛(HR)基因编码的蛋白质。该实验室已经证明，无毛(HR)蛋白影响多种核受体的功能，包括甲状腺激素受体、维生素D受体和孤儿受体ROR。HR在许多组织中发挥作用，尤其是在皮肤中，因为HR基因的突变导致人类和小鼠脱发(脱发)。我们的中心假设是，HR影响体内下游激素反应基因的表达，并且HR突变表型是由基因表达的特定变化引起的。这项拟议研究的目标之一是确定HR作为转录抑制因子的分子机制，并将包括识别与HR相互作用的特定蛋白质，包括其他核受体。确定受HR影响的信号通路将包括识别受HR调控的特定靶基因；根据我们最近的数据，候选靶基因包括Wnt信号的特定抑制物。Wnt信号通路在组织发育和动态平衡中起着至关重要的作用，而Wnt信号的中断与癌症有关。第二个目标是使用基因工程小鼠在体内测试HR功能。最近对缺乏HR表达的小鼠的分析揭示了在调节干细胞分化方面的潜在作用，这一模型将使用转基因小鼠进行测试。以皮肤为模型系统定义HR的作用将提供对不同生物过程的洞察，因为HR还影响调节大脑发育、骨形成和矿物质代谢的受体的活动。核受体已经成为治疗糖尿病等疾病的成功靶点。了解HR辅阻遏物作用的分子途径将有助于确定调节核受体功能的特定机制，这反过来可能揭示治疗发育和生理疾病的潜在干预部位。荷尔蒙通过核受体调节生长发育等生物过程。这项工作将使我们了解调节核受体功能的特定方式，这将有助于设计治疗发育和生理疾病的治疗剂。

DESCRIPTION (provided by applicant): The long term goal of this work is to understand how gene regulatory networks controlled by hormones regulate developmental and physiological processes. Nuclear receptors mediate the actions of a variety of hormones by activating the expression of specific genes. Some nuclear receptors can also repress transcription by association with corepressors, but less is known about the mechanisms and significance of repression. This study focuses on a novel nuclear receptor corepressor, the protein encoded by the mammalian Hairless (Hr) gene. This laboratory has demonstrated that the Hairless (HR) protein influences the function of multiple nuclear receptors, including thyroid hormone receptors, vitamin D receptor, and an orphan receptor, ROR. HR functions in many tissues, most prominently in skin as mutations in the Hr gene cause (alopecia) hair loss in humans and mice. Our central hypothesis is that HR influences the expression of downstream hormone-responsive genes in vivo, and that the Hr mutant phenotype arises from specific changes in gene expression. One goal of the proposed research is to determine the molecular mechanisms by which HR acts as a transcriptional represser, and will include the identification of specific proteins, including other nuclear receptors, that interact with HR. Defining the signaling pathways influenced by HR will include the identification of specific target genes that are regulated by HR; based on our recent data, candidate target genes include specific inhibitors of Wnt signaling. The Wnt signaling pathway plays an essential role in tissue development and homeostasis, and disruptions in Wnt signaling are associated with cancer. A second goal is to test HR function in vivo using genetically engineered mice. Recent analysis of mice lacking HR expression has revealed a potential role in regulating stem cell differentiation, a model that will be tested using transgenic mice. Defining the role of HR using skin as a model system will provide insight into diverse biological processes, as HR also influences the activity of receptors that mediate brain development, bone formation and mineral metabolism. Nuclear receptors are already successful therapeutic targets for the treatment of diseases such as diabetes. Understanding the molecular pathway of HR corepressor action will help define a specific mechanism of regulating nuclear receptor function, which in turn may reveal potential sites of intervention to treat developmental and physiologic disorders. Hormones regulate biological processes such as growth and development via nuclear receptors. This work will allow us to understand a specific way of regulating nuclear receptor function, which should be useful for designing therapeutic agents for treating developmental and physiologic disorders.