DAF16 HOMOLOGUES & MEDIATING COMPLICATIONS OF DIABETES

描述：(改编自申请人的摘要)在哺乳动物细胞中， IR-IGF-IR通过PI3-K/AKT(蛋白激酶B)信号转导通路 抑制某些代谢途径(抑制PEPCK和IGFBP-1基因 转录)以及细胞凋亡。然而，生理上相关的 PI3-K/PKB下游转录调控因子尚未被 已确认身份。在C线虫中，胰岛素样受体(DAF-2)或 磷脂酰肌醇-3激酶(AGE-1)基因使寿命延长两倍。 DAF-16基因的失活消除了这种额外的寿命，并缓解了 AKT信令的必要性。这表明DAF-16基因产物存在 胰岛素样信号通路中DAF-2/AGE-1下游 Akt的作用是拮抗DAF-16的功能。 研究人员建议研究DAF-16 MS在调节 胰岛素对控制肝脏糖异生的基因有负面影响， 如PEPCK，以及控制神经元和胰岛细胞凋亡的基因，如 Fas/Fas配体。提出的工作目标是描述C-elegans的特征 DAF-16蛋白及其哺乳动物同源物及胰岛素的作用 肝组织中DAF-16MS及其靶基因活性/表达的研究 胰腺。他们将研究胰岛素/营养干预对 DAF-16MS在大鼠肝脏和胰腺中的表达确定已知DNA的特征 DAF-16MS靶点的结合位点，如PEPCK和淀粉酶。请查看 胰岛素/营养干预对血管内皮细胞磷酸化活性和蛋白表达的影响 DAF-16MS的细胞定位以了解胰岛素的后果 调控糖异生的基因表达充足/缺乏 肝脏、胰腺和神经细胞的凋亡。

DESCRIPTION: (Adapted from the applicant's abstract) In mammalian cells, IR-IGF-IR signaling through PI 3-kinase/AKT (protein kinase B) is crucial for inhibition of certain metabolic pathways (inhibition of PEPCK and IGFBP-1 gene transcription) as well as apoptosis. However, the physiologically relevant transcription regulators down stream of PI 3-kinase/PKB have not been identified. In C-elegans defects in either the insulin like receptor (DAF-2) or phosphatidylinositol-3 kinase (AGE-1) genes prolongs life span by two fold. Inactivation of the DAF-16 gene abolishes this extra longevity and alleviates the need for Akt signaling. This indicates that DAF-16 gene product lies downstream of the DAF-2/AGE-1 in the insulin-like signaling pathway and that the role of Akt is to antagonize DAF-16 function. The investigator proposes to examine the role of DAF-16 MS in mediating the negative effect of insulin on genes that control gluconeogenesis in the liver, such as PEPCK, and genes that control apoptosis in neurons and islet, such as Fas/Fas ligand. The goal of the work proposed is to characterize the C-elegans DAF-16 protein and its mammalian homologues and to assess the effect of insulin on the activity/expression of DAF-16 MS and their target genes in liver and pancreas. They will Examine the effect of insulin/nutritional manipulations on expression of DAF-16 MS in rat liver and pancreas. Characterize known DNA binding sites in targets of DAF-16 MS, such as PEPCK and amylase. Examine the effect of insulin/nutritional manipulations on the phosphorylation activity and cellular location of DAF-16 MS so as to understand the consequences of insulin sufficiency/lack on expression of genes that regulate gluconeogenesis in the liver and apoptosis in pancreas and neuronal cells.