Regulation of Hepatic Gluconeogenesis by the CREB:TORC2 Pathway

项目摘要/摘要 转录因子CREB(cAMP反应元件结合蛋白)调节代谢基因表达 以应对cAMP信号的增加。CREB被认为可以促进多达5000个基因的表达 哺乳动物基因组，但CREB激活不同靶基因的机制不同 具体情况仍不明朗。为了解决这个问题，Montminy实验室将分析CREB信令输出 肝脏和胰岛，因为CREB在这两个组织中的活性对葡萄糖稳态是必不可少的。在.期间 禁食期间，循环中胰高血糖素的增加会触发肝脏中糖异生基因的表达 通过诱导CREB途径。在进食过程中，肠道内分泌细胞分泌类胰高血糖素。 多肽1(GLP1)，刺激胰岛素分泌和促进β细胞活性，也通过CREB- 依赖机制。平衡这两个相反的CREB介导的生理过程出现了 对葡萄糖动态平衡至关重要。组蛋白乙酰转移酶共激活剂CBP刺激CREB活性 和P300，以及cAMP调节的转录辅活化子(CRTC)家族，它们与 CREB回应夏令营。在这里，不同的CRTC和转录辅助因子在调控中的作用 CREB/CRTC的活性，以引起组织特异性反应(即，肝脏与胰岛)将被检测。这个 总体假设是CREB途径作为肝脏葡萄糖产生和分泌的中枢调节因子发挥作用 胰腺胰岛素分泌。目标1将重点介绍CREB介导的肝脏葡萄糖产生 禁食。蒙明尼实验室将培育出缺乏CRTC2和CRTC3(单独和联合)的小鼠。 特别是在肝细胞中，并评估对葡萄糖输出的影响。然后，实验室将审查 转录因子FOXO1和表观遗传调节因子BRD4促进CRTC重新整合到 禁食诱导的肝细胞基因。目的2将探讨CRTC1和CRTC2在调节 葡萄糖和GLP1对胰岛素分泌和β细胞活性的影响。实验室将产生缺乏的小鼠 CRTc1和CRTC2(单独和联合)在胰岛β细胞中的特异性并评估其作用 胰岛素分泌和CREB靶基因的选择。该实验室将表征贝塔细胞所扮演的角色- 特异性转录因子NeuroD1和cAMP调节的非编码RNA LINC00473在增强中的作用 胰腺中的CREB/CRTC信号转导。拟议的研究将揭示CREB和CREB之间的相互作用， CRTC及其辅因子(如谱系特异性转录因子和表观遗传调节因子)促进 差异激活CREB靶基因在肝脏和胰腺中的糖稳态 小岛。通过化学抑制剂靶向这些辅因子，可能会为患有以下类型的患者提供治疗益处 二、糖尿病。

Project Summary/Abstract The transcription factor CREB (cAMP response element-binding protein) regulates metabolic gene expression in response to increases in cAMP signaling. CREB is thought to promote the expression of up to 5000 genes in the mammalian genome, but mechanisms by which CREB activates different sets of target genes in different contexts remain unclear. To address this problem, the Montminy lab will analyze CREB signaling output in the liver and pancreatic islets, as CREB activity in these two tissues is essential for glucose homeostasis. During periods of fasting, increases in circulating glucagon trigger the expression of gluconeogenic genes in the liver via induction of the CREB pathway. During feeding, intestinal enteroendocrine cells secrete glucagon like peptide 1 (GLP1), which stimulates insulin secretion and promotes beta cell viability, also via a CREB- dependent mechanism. Balancing these two opposing CREB-mediated physiological processes appears critical for glucose homeostasis. CREB activity is stimulated by the histone acetyl-transferase coactivators CBP and P300, and by a family of cAMP regulated transcriptional coactivators (CRTCs), which associate with CREB in response to cAMP. Here, the roles of different CRTCs and transcriptional co-factors in modulating CREB/CRTC activity to elicit tissue-specific responses (i.e., hepatic vs. pancreatic islet) will be examined. The overall hypothesis is that the CREB pathway functions as a central regulator of hepatic glucose production and pancreatic insulin secretion. Aim 1 will focus on CREB-mediated glucose production by the liver in response to fasting. The Montminy lab will generate mice lacking CRTC2 and CRTC3 (alone and in combination) specifically in hepatocytes and assess effects on glucose output. The lab will then examine roles played by the transcription factor FOXO1 and the epigenetic regulator BRD4 in facilitating CRTC recruitment to a subset of fasting-induced genes in hepatocytes. Aim 2 will explore the role of CRTC1 and CRTC2 in mediating the effects of glucose and GLP1 on insulin secretion and beta cell viability. The lab will generate mice lacking CRTC1 and CRTC2 (alone and in combination) specifically in pancreatic islet beta cells and assess the effects on insulin secretion and CREB target gene selection. The lab will characterize roles played by the beta cell- specific transcription factor NeuroD1 and the cAMP-regulated non-coding RNA, LINC00473, in potentiating CREB/CRTC signaling in the pancreas. The proposed studies will uncover how interactions between CREB, CRTCs, and their cofactors (e.g., lineage-specific transcription factors and epigenetic regulators) promote glucose homeostasis by differentially activating specific subsets of CREB target genes in liver and pancreatic islets. Targeting these cofactors via chemical inhibitors may provide therapeutic benefit to individuals with type II diabetes.