Molecular regulation of glucose metabolism by orphan nuclear receptors

这项研究的目的是确定孤儿核受体控制葡萄糖代谢相关基因的激活和抑制的新机制。肝脏X受体α(LXRa)的激活抑制了参与葡萄糖代谢的关键基因的表达，其中包括葡萄糖合成的限速酶，磷酸烯醇式丙酮酸羧激酶(PEPCK)。本实验室的初步数据还表明，肝脏X受体β(LXRb)是糖皮质激素(GC)介导的PEPCK上调所必需的，这表明核受体糖皮质激素受体和LXRs之间正在发生一种重要的、目前尚不清楚的分子相互作用。第一个目标将是确定LXRa介导的涉及葡萄糖代谢的基因反转录的分子机制。第二个目标是确定GC和孤儿核受体LXRb在控制葡萄糖代谢中相互作用的新机制。使用复杂的基因组和蛋白质组分析技术，我们将确定LXRs是否直接调控GC反应基因，或者这种影响是否次要于另一种中间蛋白的改变调控。我们将确定这些核受体是否与这些活性启动子相关，以及它们在启动子上下文中的位置。这项研究计划具有识别全新的GC信号和血糖调节的分子机制的重要作用，并有可能揭示该受体超家族的成员如何在分子水平上聚集在代谢信号通路上。加拿大的好处不仅在于改善了受训者的研究环境，提高了加拿大研究质量的知名度，而且还在于发现了调节至关重要的葡萄糖代谢过程的新分子成分。

The objective of this research program is to identify novel mechanisms by which orphan nuclear receptors control the activation and repression of genes involved in glucose metabolism. Activation of the liver X receptor alpha (LXRa) inhibits the expression of key genes involved in glucose metabolism including the rate-limiting enzyme in glucose synthesis, phosphoenolpyruvate carboxykinase (PEPCK). Preliminary data from this lab have also demonstrated that the liver X receptor beta (LXRb) is required for the glucocorticoid (GC)-mediated upregulation of PEPCK, suggesting that an important and currently unrecognized molecular interplay is occurring between the nuclear receptors glucocorticoid receptor and the LXRs. The first objective will be to determine the molecular mechanism of LXRa-mediated transrepression of genes involved in glucose metabolism. The second objective will be to identify novel mechanisms of interaction between GC and the orphan nuclear receptor LXRb in the control of glucose metabolism. Using sophisticated technology for genomic and proteomic analysis, we will determine whether direct regulation of GC-responsive genes is occurring with LXRs or whether the effect is secondary to altered regulation of another intermediate protein. We will determine whether or not these nuclear receptors are associated with these active promoters and where they are located in the promoter context. This research program has the important function of identifying completely novel molecular mechanisms for GC signaling and glucose regulation with a high probability for uncovering how members of this receptor superfamily converge at the molecular level on metabolic signaling pathways. The benefit to Canada will come not only in the form of an enhanced research environment for trainees and increased visibility in the quality of research in Canada but also in the discovery of new molecular components regulating the critically important process of glucose metabolism.