DAF16 HOMOLOGUES & MEDIATING COMPLICATIONS OF DIABETES

DAF16 同系物

• 批准号: 6053979
• 负责人: MARIA Carmalita ALEXANDER-BRIDGES
• 金额: $ 17.1万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-09-30 至 2001-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6053979
• 关键词: DNA footprinting; apoptosis; diabetes mellitus; gene expression; genetic library; gluconeogenesis; insulin; laboratory mouse; laboratory rat; liver; medical complication; molecular pathology; neurons; pancreas; phosphatidylinositol 3 kinase; phosphorylation; protein kinase; protein structure function; site directed mutagenesis; transcription factor

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.

描述：（改编自申请人的摘要）在哺乳动物细胞中， 通过PI 3-激酶/AKT（蛋白激酶B）的IR-IGF-IR信号传导对于至关重要 抑制某些代谢途径（抑制PEPCK和IGFBP-1基因 转录）以及凋亡。但是，生理上相关的 pi 3-激酶/pkb的转录调节器尚未 确定。在胰岛素像受体（DAF-2）或 磷脂酰肌醇-3激酶（Age-1）基因延长了两倍的寿命。 DAF-16基因的失活消除了这种额外的寿命并减轻 需要AKT信号。这表明DAF-16基因产品位于 胰岛素样信号通路中DAF-2/AGE-1的下游， AKT的作用是拮抗DAF-16功能。 研究人员建议检查DAF-16 MS在中介中的作用 胰岛素对控制肝中糖异生的基因的负面影响， 例如PEPCK以及控制神经元和胰岛凋亡的基因，例如 FAS/FAS配体。提出的工作的目的是表征C-电子 DAF-16蛋白及其哺乳动物同源物并评估胰岛素的作用 关于DAF-16 MS的活性/表达及其在肝脏中的靶基因 胰腺。他们将检查胰岛素/营养操纵对 大鼠肝脏和胰腺中DAF-16 MS的表达。表征已知的DNA DAF-16 MS的靶标（例如PEPCK和淀粉酶）中的结合位点。检查 胰岛素/营养操纵对磷酸化活性和 DAF-16 MS的细胞位置，以了解胰岛素的后果 充分/缺乏调节糖异生基因的表达 胰腺和神经元细胞中的肝脏和凋亡。