Role of a Novel Corepressor in Nuclear Receptor Action

描述（由申请人提供）：这项工作的长期目标是了解激素控制的基因调控网络如何调节发育和生理过程。核受体通过激活特定基因的表达来介导多种激素的作用。一些核受体也可以通过与辅阻遏物结合来抑制转录，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物，蛋白质编码的哺乳动物无毛（Hr）基因。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在许多组织中起作用，最突出的是在皮肤中，因为Hr基因的突变导致人类和小鼠的脱发。我们的中心假设是，HR影响下游的表达，应答基因在体内，和HR突变表型产生的基因表达的特定变化。这项研究的目标之一是确定HR作为转录抑制因子的分子机制，并将包括鉴定与HR相互作用的特定蛋白质，包括其他核受体。基于我们最近的数据，候选靶基因包括Wnt信号传导的特异性抑制剂。Wnt信号通路在组织发育和体内平衡中起着重要作用，并且Wnt信号通路的破坏与癌症相关。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中的潜在作用，这是一种将使用转基因小鼠进行测试的模型。使用皮肤作为模型系统来定义HR的作用将提供对不同生物过程的深入了解，因为HR还影响介导大脑发育、骨形成和矿物质代谢的受体的活性。核受体已经是治疗糖尿病等疾病的成功治疗靶点。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障碍的潜在干预位点。激素通过核受体调节生物过程，如生长和发育。这项工作将使我们能够了解一个特定的方式来调节核受体的功能，这应该是有用的设计治疗药物治疗发育和生理障碍。

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.