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MECHANISM OF IGF-I EFFECTS ON CHROMAFFIN CELL FUNCTION

IGF-I影响嗜铬细胞功能的机制

基本信息

批准号：
2016392
负责人：
Mary K Dahmer
金额：
$ 10.77万
依托单位：
UNIVERSITY OF TENNESSEE HEALTH SCI CTR
依托单位国家：
美国
项目类别：
财政年份：
1992
资助国家：
美国
起止时间：
1992-09-30 至 1998-09-29
项目状态：
已结题

项目摘要

Insulin-like growth factor-I (IGF-I) has been reported to act as a trophic factor which enhances functions associated with the differentiated phenotype of many cells. Often IGF-I appears to modulate the activity of the cells with little, or no, effect on proliferation. In adrenal chromaffin cells, IGF-I enhances secretagogue-stimulated catecholamine secretion and Ca2+ uptake into the cells. The long-term objective of this project is to elucidate the mechanism by which IGF-I exerts its trophic effects on cell function. The studies described in this grant will investigate the mechanism by which chronic exposure to IGF-I enhances secretagogue-stimulated catecholamine secretion from chromaffin cells. We will examine the hypothesis that IGF-I enhances secretion by activating one of the isozymes of protein kinase C. The generality of the role of protein kinase C in IGF-I action will be explored using the effect of IGF-I on steroidogenesis in adrenocortical cells as another model system. Because catecholamines are important as hormones and neurotransmitters in the peripheral and central nervous system, this work will increase our understanding not only of the regulation of chromaffin cell function, but also of the regulation of those processes, such as blood pressure and cardiovascular function, that are regulated by catecholamines. In addition, understanding the trophic effects of IGF-I, such as steroidogenesis. The specific aims of the proposed research are: 1. To determine whether protein kinase C is required for IGF-I enhanced catecholamine secretion from chromaffin cells. Cells in which protein kinase C activity is suppressed either by inhibitors or by down regulation will be used to determine whether protein kinase C is involved in IGF-I action. 2. To determine how protein kinase C is involved in the effect of IGF-I on secretion from chromaffin cells. The effect of IGF-I on the activity of protein kinase C, and the effect of phorbol esters and protein kinase C inhibitors on the function of IGF-I receptors will be examined. 3. To determine whether the effect of IGF-I on protein kinase C is responsible for enhanced Ca2+ uptake in IGF-I treated chromaffin cells and to determine whether such an effect causes the enhanced secretion seen in IGF-I treated cells. Ca2+ uptake and efflux experiments will be performed in untreated and IGF-I treated cells made deficient in protein kinase C activity. 4. To determine whether protein kinase C is involved in the effect of IGF-I on ACTH stimulated cAMP accumulation and cortisol synthesis in adrenocortical cells. Adrenocortical cells in which protein kinase C activity is suppressed either by inhibitors or by down regulation will be used to determine whether protein kinase C is involved in IGF-I action in these cells.

胰岛素样生长因子-I(IGF-I)已被报道起营养作用。增强与差异化产品相关的功能的因素许多细胞的表型。通常情况下，IGF-I似乎调节血管活性。对增殖影响很小或没有影响的细胞。在肾上腺嗜铬细胞，IGF-I增强促分泌剂刺激儿茶酚胺分泌和细胞内的钙摄取。这样做的长期目标是该项目旨在阐明IGF-I发挥其营养作用的机制对细胞功能的影响。这笔赠款中描述的研究将研究长期暴露于IGF-I可增强作用的机制促分泌剂刺激嗜铬细胞分泌儿茶酚胺。我们将检验IGF-I通过激活一种激素来促进分泌的假设蛋白激酶C同工酶的作用的共性将利用IGF-I的作用来探讨IGF-I中的激酶C的作用作为另一个模型系统的肾上腺皮质细胞中的类固醇合成。因为儿茶酚胺是人体内重要的激素和神经递质。外周和中枢神经系统，这项工作将增加我们的不仅了解嗜铬细胞功能的调节，而且以及对这些过程的调节，如血压和心血管功能，由儿茶酚胺调节。在……里面此外，了解IGF-I的营养作用，如类固醇合成。拟议研究的具体目标是：1. 确定IGF-I增强是否需要蛋白激酶C 嗜铬细胞分泌儿茶酚胺。细胞中的蛋白质激酶C的活性被抑制剂或下调抑制将用于确定蛋白激酶C是否参与IGF-I 行动。2.确定蛋白激酶C如何参与 IGF-I对嗜铬细胞分泌的影响。胰岛素样生长因子-I对血管内皮细胞生长的影响蛋白激酶C的活性及佛波酯和蛋白质的影响将检测对IGF-I受体功能的激酶C抑制剂。3. 确定IGF-I对蛋白激酶C的影响是否与 IGF-I促进嗜铬细胞钙摄取的实验研究这种效应是否会导致IGF-I治疗后的分泌增加细胞。将在未经处理的患者中进行钙吸收和外流实验而IGF-I处理的细胞使蛋白激酶C活性降低。4.至确定蛋白激酶C是否参与IGF-I对血管内皮细胞的影响 ACTH刺激肾上腺皮质cAMP积聚和皮质醇合成细胞。蛋白激酶C活性较高的肾上腺皮质细胞被抑制剂或下调调控抑制，将被用来确定蛋白激酶C是否参与胰岛素样生长因子-I的作用细胞。