PHOSPHOINOSITIDE HYDROLYSIS AND BETA CELL SECRETION
磷酸肌醇水解和 β 细胞分泌
基本信息
- 批准号:6517161
- 负责人:
- 金额:$ 30.89万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:1989
- 资助国家:美国
- 起止时间:1989-05-01 至 2003-06-30
- 项目状态:已结题
- 来源:
- 关键词:Adenoviridae biological signal transduction body weight cyclic AMP dexamethasone enzyme activity fasting genetic transduction genetically modified animals glucose glucose metabolism hydrolysis inositol phosphates insulin isozymes laboratory mouse laboratory rat pancreatic islet function pancreatic islets phosphatidylinositols phospholipase C protein kinase C secretion transfection /expression vector western blottings
项目摘要
The regulation of glucose homeostasis depends on the secretion of
insulin from the pancreatic beta-cell in amounts commensurate to satisfy
peripheral tissue requirements. Playing a strategic role in the
regulation of insulin release in the phospholipase C (PLC)/protein
kinase C (PKC) transduction system. Islets of Langerhans contain the
three major isozymes of PLC(beta1, gamma1 and delta1) and the calcium-
dependent PKC isozyme, PKCalpha. Species differences in the content and
activation of PLC and PKC have been identified and these differences
play a major role in regulating the response to glucose. For example,
rat islets contain 5 times as much PLCdelta1 as do mouse islets and in
response to glucose stimulation inositol phosphates (IPs), a marker for
PLC activation, increase 400%. The activation of PLC in rat islets is
paralleled by a rising 30-fold increase in second phase release. In
contrast, mouse islet responses to glucose are notable for the minimal
activation of PLC and the small, flat second phase insulin secretory
response. Rat and human islets, but not mouse islets, can be sensitized
by prior short term exposure to glucose, a process termed time-dependent
potentiation (TDP), or they can be desensitized by long term exposure to
glucose, referred to as glucose toxicity or time-dependent suppression
(TDS). The immunity of mouse islets to these multiple effects of glucose
is a consequence of glucose's inability to activate PLC: significant
increases in PLC activation, second phase insulin secretion and the
induction of both TDP and TDS result when mouse islets are stimulated
with carbachol, an agonist that significantly activates an isozyme of
PLC distinct from that activated by glucose. These and other
observations have led us to conclude that PLC/PKC activation regulates
physiologic insulin secretion and that disordered PLC/PKC signaling
culminates in disordered insulin secretion. Experiments described
critically test this concept using rat and mouse islets. We will also
treat cultured rat or mouse islets with adenoviral vectors containing
the cDNAs for the isozymes of PLC and to determine if the increased
expression and subsequent activation of these enzymes reestablishes
sensitivity to glucose. Finally, the impact of the regulated over-
expression of the major PLC isozymes and PKCalpha (using a reverse
tetracycline-controlled transactivator system) on in vivo glucose
homeostasis and in vitro sensitivity to stimulation will be determined
in transgenic mice. These studies will define the role of PLC/PKC
activation in regulating islet response patterns to glucose stimulation
and they may facilitate the development of genetically-engineered cell
lines designed to replace missing of defective beta-cells.
葡萄糖动态平衡的调节依赖于分泌
来自胰腺β细胞的胰岛素,其数量与满足
外周组织要求。在全球经济一体化中发挥战略作用
磷脂酶C(PLC)/蛋白对胰岛素释放的调节
蛋白激酶C(PKC)转导系统。朗格汉斯的小岛上有
PLC的三种主要同工酶(Beta1、Gamma1和Delta1)和钙离子-
依赖的PKC同工酶,PKCalpha。含量和含量的物种差异
已经确定了PLC和PKC的激活以及这些差异
在调节对葡萄糖的反应方面起着重要作用。例如,
大鼠胰岛含有的PLCdelta1是小鼠胰岛的5倍,在
对葡萄糖刺激的反应肌醇磷酸盐(IPs)是一种
激活PLC,增加400%。大鼠胰岛细胞内PLC的激活
与之相对应的是,第二阶段的释放增加了30倍。在……里面
相比之下,小鼠胰岛对葡萄糖的最小反应值得注意
PLC的激活与小而平坦的第二相胰岛素分泌
回应。大鼠和人的胰岛可以致敏,但小鼠的胰岛不能致敏
由于先前短期接触葡萄糖,这一过程被称为时间依赖
增强(TDP),或它们可以通过长期暴露于
葡萄糖,称为葡萄糖毒性或时间依赖性抑制
(TDS)。小鼠胰岛对葡萄糖多种作用的免疫力
是葡萄糖无法激活PLC的后果:意义重大
PLC激活、第二时相胰岛素分泌增加和
当小鼠胰岛被刺激时,TDP和TDS的诱导都会产生
使用卡巴胆碱,一种激动剂,显著激活
PLC不同于由葡萄糖激活的PLC。这些和其他
观察结果使我们得出结论,PLC/PKC激活调节
生理性胰岛素分泌与PLC/PKC信号转导紊乱
最终导致胰岛素分泌紊乱。所描述的实验
用大鼠和小鼠的胰岛对这一概念进行批判性的测试。我们还将
用腺病毒载体治疗培养的大鼠或小鼠胰岛
对PLC同工酶的cDNA进行检测,以确定是否增加了
这些酶的表达和随后的激活重新建立
对葡萄糖敏感。最后,监管过度的影响-
主要PLC同工酶和PKCalpha的表达(使用反向
四环素控制的反式激活系统)对体内葡萄糖的影响
动态平衡和体外对刺激的敏感性将被确定
在转基因小鼠身上。这些研究将确定PLC/PKC的作用
调节胰岛对葡萄糖刺激反应模式的激活
它们可能会促进基因工程细胞的发展
设计用来替换缺失的缺陷β细胞的线条。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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WALTER S. ZAWALICH其他文献
WALTER S. ZAWALICH的其他文献
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{{ truncateString('WALTER S. ZAWALICH', 18)}}的其他基金
PHOSPHOINOSITIDE HYDROLYSIS AND BETA CELL SECRETION
磷酸肌醇水解和 β 细胞分泌
- 批准号:
6380613 - 财政年份:1989
- 资助金额:
$ 30.89万 - 项目类别:
PHOSPHOINOSITIDE HYDROLYSIS AND BETA CELL SECRETION
磷酸肌醇水解和 β 细胞分泌
- 批准号:
7056109 - 财政年份:1989
- 资助金额:
$ 30.89万 - 项目类别:
PHOSPHOINOSITIDE HYDROLYSIS AND BETA CELL SECRETION
磷酸肌醇水解和 β 细胞分泌
- 批准号:
2141650 - 财政年份:1989
- 资助金额:
$ 30.89万 - 项目类别:
PHOSPHOINOSITIDE HYDROLYSIS AND BETA CELL SECRETION
磷酸肌醇水解和 β 细胞分泌
- 批准号:
6892079 - 财政年份:1989
- 资助金额:
$ 30.89万 - 项目类别:
PHOSPHOINOSITIDE HYDROLYSIS AND BETA CELL SECRETION
磷酸肌醇水解和 β 细胞分泌
- 批准号:
2141652 - 财政年份:1989
- 资助金额:
$ 30.89万 - 项目类别:
PHOSPHOINOSITIDE HYDROLYSIS AND BETA CELL SECRETION
磷酸肌醇水解和 β 细胞分泌
- 批准号:
2414796 - 财政年份:1989
- 资助金额:
$ 30.89万 - 项目类别:
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