INSULIN SIGNALING PATHWAYS REGULATING HEPATIC METABOLIS

调节肝脏代谢的胰岛素信号通路

• 批准号: 2518180
• 负责人: ROBERT A GABBAY
• 金额: $ 5.13万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-09-30 至 1998-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2518180
• 关键词: Adenoviridae; RNase protection assay; biological signal transduction; carbohydrate metabolism; enzyme activity; genetic regulation; genetic transcription; gluconeogenesis; glycogen synthase; hormone regulation /control mechanism; insulin; insulin sensitivity /resistance; laboratory mouse; laboratory rat; lipid metabolism; liver cells; liver metabolism; mitogen activated protein kinase; northern blottings; phosphatidylinositol 3 kinase; phosphorylation; pyruvate kinase; reporter genes; tissue /cell culture; very low density lipoprotein

DESCRIPTION (Taken from the applicant's Abstract) Non-insulin dependent diabetes mellitus affects nearly 10 million Americans and costs the United States more than $20 billion a year. The specific molecular lesions responsible for the insulin resistance characteristic of this disease remain unknown. Recently, great progress has been made in identifying the initial signaling events in insulin action; however, the role of these molecules in the metabolic effects of insulin remains to be determined. The liver plays a central role in the regulation of carbohydrate and lipid metabolism, and hepatic insulin resistance is critical to the development of two of the clinical hallmarks of diabetes -- fasting hyperglycemia and hypertriglyceridemia. The goal of this study is to examine the role of the two best-characterized components of the insulin signal transduction system (phosphatidylinositol 3- kinase and the ras/MAP kinase pathway) in the regulation of hepatic carbohydrate and lipid metabolism. We will develop several methods to alter these signaling pathways (i.e., adenoviral vector infection, generation of inducible promoter stable transfectants) and examine the effects these specific perturbations on defined targets of hepatic insulin action in both isolated cell systems and in vivo using mouse models. Dr. Gabbay has a long-standing interest in the pathogenesis of diabetes, hepatic insulin action, and insulin resistance. This project will be conducted in the Endocrine Division of Beth Israel Hospital, Boston under the supervision of Dr. Jeffrey Flier. A major focus within the Division is the molecular dissection of the mechanisms underlying insulin resistance. The research environment provides state-of-the-art molecular biological and animal research facilities.

描述（摘自申请人摘要） 非胰岛素依赖型糖尿病影响近1000万美国人 每年花费美国超过200亿美元。 具体 胰岛素抵抗的分子损伤 这种疾病仍然未知。 最近，在以下方面取得了很大进展： 识别胰岛素作用中的初始信号事件;然而， 这些分子在胰岛素代谢效应中的作用仍有待进一步研究。 测定 肝脏在调节 碳水化合物和脂质代谢，以及肝脏胰岛素抵抗， 对糖尿病的两个临床标志的发展至关重要-- 空腹高血糖和高甘油三酯血症。 本研究的目的是探讨两个最好的特点的作用， 胰岛素信号转导系统的组分（磷脂酰肌醇 3-激酶和ras/MAP激酶途径）在肝细胞凋亡调控中的作用 碳水化合物和脂质代谢。 我们将开发几种方法来改变 这些信号通路（即，腺病毒载体感染，产生 诱导型启动子稳定的转染子），并检查这些 对肝脏胰岛素作用的特定靶点的特异性干扰， 分离的细胞系统和体内使用小鼠模型。 博士Gabbay对糖尿病的发病机制有着长期的兴趣， 肝脏胰岛素作用和胰岛素抵抗。 该项目将 在波士顿Beth Israel医院内分泌科进行， 杰弗里·弗里尔医生的监督 该司的一个主要重点是 对胰岛素抵抗机制的分子解剖。 研究环境提供了最先进的分子生物学和 动物研究设施。