DAF16 HOMOLOGUES & MEDIATING COMPLICATIONS OF DIABETES

DAF16 同系物

• 批准号: 6178227
• 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/6178227
• 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 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，与生理相关的 PI 3-激酶/PKB下游的转录调节因子尚未被研究 确定。线虫中胰岛素样受体 (DAF-2) 或 磷脂酰肌醇-3 激酶 (AGE-1) 基因可将寿命延长两倍。 DAF-16 基因的失活消除了这种额外的寿命并减轻了 Akt 信号传导的需要。这表明 DAF-16 基因产物位于 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 的功能。 研究人员建议检查 DAF-16 MS 在调节 胰岛素对控制肝脏糖异生的基因的负面影响， 例如 PEPCK，以及控制神经元和胰岛细胞凋亡的基因，例如 Fas/Fas 配体。拟议工作的目标是描述线虫的特征 DAF-16蛋白及其哺乳动物同源物并评估胰岛素的效果 DAF-16 MS 及其靶基因在肝脏和肝脏中的活性/表达的影响 胰腺。他们将检查胰岛素/营养操作对 DAF-16 MS 在大鼠肝脏和胰腺中的表达。表征已知 DNA DAF-16 MS 靶标中的结合位点，例如 PEPCK 和淀粉酶。检查 胰岛素/营养操作对磷酸化活性的影响和 DAF-16 MS 的细胞定位，以了解胰岛素的后果 调节糖异生的基因表达充足/缺乏 肝脏以及胰腺和神经元细胞的凋亡。