DAF16 HOMOLOGUES & MEDIATING COMPLICATIONS OF DIABETES

描述：（改编自申请人摘要）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）以及凋亡。然而，生理相关的 PI 3-激酶/PKB下游的转录调节因子尚未被发现。 鉴定在秀丽隐杆线虫中，胰岛素样受体（β 2）或 磷脂酰肌醇-3激酶（AGE-1）基因使寿命延长两倍。 灭活β-16基因会消除这种额外的寿命， Akt信号的需要。这表明，P16基因产物存在于 在胰岛素样信号传导途径中位于β 2/AGE-1的下游， Akt的作用是拮抗β 16的功能。 研究者建议检查α-16 MS在介导 胰岛素对控制肝脏中胰岛素生成的基因的负面影响， 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。这项工作的目标是描述线虫的特征 目的：研究胰岛素对人β-16蛋白及其哺乳动物同源物的影响， 对肝脏中的β-16 MS及其靶基因的活性/表达的影响， 胰腺他们将检查胰岛素/营养操作对 在大鼠肝脏和胰腺中的表达。描述已知DNA 结合位点，如PEPCK和淀粉酶。检查 胰岛素/营养操作对磷酸化活性的影响， 细胞定位的β-16 MS，以便了解胰岛素的后果 足够/缺乏的基因表达调节胚胎发育， 胰腺和神经细胞凋亡。

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.