Molecular regulation of glucose metabolism by orphan nuclear receptors

孤儿核受体对葡萄糖代谢的分子调节

• 批准号: 356873-2008
• 负责人: Cummins, Carolyn
• 金额: $ 2.26万
• 依托单位: University of Toronto
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2011
• 资助国家: 加拿大
• 起止时间: 2011-01-01 至 2012-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=483102
• 关键词: Molecular; regulation; glucose; metabolism; orphan

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.

该研究计划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) 的激活会抑制参与葡萄糖代谢的关键基因的表达，包括葡萄糖合成中的限速酶磷酸烯醇丙酮酸羧激酶 (PEPCK)。 该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 LXR 之间正在发生重要且目前尚未认识到的分子相互作用。第一个目标是确定 LXRa 介导的葡萄糖代谢基因反式抑制的分子机制。 第二个目标是确定 GC 和孤儿核受体 LXRb 之间在控制葡萄糖代谢中相互作用的新机制。 使用先进的基因组和蛋白质组分析技术，我们将确定 LXR 是否直接调节 GC 响应基因，或者该效应是否继发于另一种中间蛋白调节的改变。 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环境中的位置。 该研究项目的重要功能是确定GC信号传导和葡萄糖调节的全新分子机制，并很有可能揭示该受体超家族的成员如何在分子水平上聚合代谢信号传导途径。对加拿大的好处不仅在于为学员提供更好的研究环境和提高加拿大研究质量的可见度，而且还在于发现调节至关重要的葡萄糖代谢过程的新分子成分。