INSULIN SIGNALING PATHWAYS REGULATING HEPATIC METABOLIS

描述(摘自申请人的摘要) 非胰岛素依赖型糖尿病影响近1000万美国人 每年给美国造成超过200亿美元的损失。具体的 胰岛素抵抗特征的分子损害 这种疾病仍不为人所知。最近，在……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研究 下定决心。肝脏在调节心脏功能中起着核心作用。 碳水化合物和脂肪代谢，肝脏胰岛素抵抗 对糖尿病的两个临床特征的发展至关重要 空腹高血糖和高甘油三酯血症。 这项研究的目的是考察这两个最具特点的角色 胰岛素信号转导系统的组成部分(磷脂酰肌醇 3-激酶和ras/MAP激酶通路)在肝脏调节中的作用 碳水化合物和脂肪代谢。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 可诱导启动子稳定的转染体)，并检测这些 大鼠肝脏胰岛素作用靶点的特异性扰动 分离的细胞系统和体内使用的小鼠模型。 加贝博士长期以来一直对糖尿病的发病机制感兴趣， 肝脏胰岛素的作用，与胰岛素抵抗。这个项目将是 在波士顿贝丝以色列医院内分泌科进行 杰弗里·弗利尔博士的监督。该司内部的一个主要重点是 对胰岛素抵抗潜在机制的分子剖析。 研究环境提供了最先进的分子生物学和 动物研究设施。

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.