REGULATION OF ALS AND ITS ROLE IN THE IGF SYSTEM

长期的目标是了解人的生理学 胰岛素样生长因子系统。IGF系统对以下各项至关重要 正常生长发育。各种缺陷中的 IGF系统的组成部分已经在癌症中被识别出来， 糖尿病和营养不良。除了经典的相互作用 受体、IGF-I和IGF-II是IGF系统的配体 与六种称为胰岛素样生长的可溶性载体蛋白相关 因子结合蛋白(IGFBP1-6)。出生后，功能性IGF 运输单元实际上是一个三元复合体，由 胰岛素样生长因子与胰岛素样生长因子结合蛋白-3和第三种名为 酸不稳定亚单位(ALS)。本应用程序的重点是ALS 因为目前的证据表明，肌萎缩侧索硬化症决定了腓肠肌 IGF-I和IGF-II的水平及其向靶组织的传递。生长 激素是控制ALS循环水平的主要因素。 然而，这一规定背后的机制并没有 已经被定义了。这项提案涉及增长的本质 肌萎缩侧索硬化的激素调节及其在体内的作用。具体目标 方法是： 1.确定生长激素的作用机制 调节小鼠肝脏中ALS mRNA的丰度。这 将通过比较肝脏中ALS mRNA的丰度来完成 以及基因在不同生长状态下的转录速率 荷尔蒙状况。 2.定义顺式元件的5‘上游区域 介导生长激素和基础激活的ALS基因 抄写。这将通过将基因导入肝细胞来完成。 ALS基因启动子驱动的荧光素酶微型菌。 3.研究ALS蛋白在体内的功能。这将是 由获得并研究ALS蛋白的小鼠完成的 缺席。这些小鼠将由基因敲除产生 接近。

The long term objective is to understand the physiology of the insulin-like growth factor system. The IGF system is essential to normal growth and development. Defects in the various components of the IGF system have been identified in cancer, diabetes and undernutrition. In addition to the classical interaction with receptors, IGF-I and IGF-II the ligands of the IGF system associate with six soluble carrier proteins called insulin-like growth factor binding protein (IGFBP1-6). Postnatally, the functional IGF transporting unit is actually a ternary complex formed by association of IGF with IGFBP-3 and a third protein called acid-labile subunit (ALS). The focus of this application is on ALS because current evidence suggests that ALS determines surum levels of IGF-I and -II and their delivery to target tissue. Growth hormone is a major factor controlling the circulating levels of ALS. The mechanisms underlying this regulation, however, have not been defined. This proposal addresses the nature of growth hormone regulation of ALS and its role in vivo. The specific aims and methods are: 1. To determine themechanism by which growth hormone regulates the abundance of ALS mRNA in the liver of mice. This will be done by comparing in liver the abundance of ALS mRNA and the rate of transcription of the gene under different growth hormone status. 2. To define the cis-elements in the 5' upstream region of the ALS gene that mediate the growth hormone and basal activation of transcription. This will be done by transfecting into liver cells luciferase minigenes driven by the promoter of the ALS gene. 3. To study the fuction of the ALS protein in vivo. This will be done by obtaineng and studying mice in which the ALS protein is absent. These mice iwll be created by the gene knockout approach.