DYNORPHIN AND BETA CELL SENSITIZATION
强啡肽和 β 细胞致敏
基本信息
- 批准号:2906354
- 负责人:
- 金额:$ 17.29万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:1998
- 资助国家:美国
- 起止时间:1998-09-30 至 2000-09-29
- 项目状态:已结题
- 来源:
- 关键词:
项目摘要
In this project, the PI proposes a series of experiments to determine
whether dynorphin and related peptides, acting through a mechanism
independent of the protein-coupled opioid receptors, synergize with
glucose to stimulate insulin secretion from beta cells of the pancreatic
islets of Langerhans. The following hypothesis will be tested.
Dynorphin sensitizes beta cells to glucose-induced insulin secretion by
activating (or prolonging the activation of) N-methyl-D-aspartate
(NMDA)-selective excitatory ionotropic glutamate receptors. Dynorphin
A is a member of the family of opioid peptides that appear to act
primarily as neuromodulators by interacting with G protein-coupled
receptors (GPCRs); mu and kappa and NMDA receptors are members of a
class of ligand-gated ion channels that when activated increase the
permeability of the cell surface membrane to Ca2+ (and Na+ and K+) and
thereby elevate cytoplasmic free Ca 2+ concentration. Elevations in
cytoplasmic free C2+ will in turn sensitize the cell to stimulation by
glucose and couple stimulation to insulin secretion.
The Specific Aims that will be pursued are: 1) To determine whether
dynorphin and related peptides synergize with glucose stimulation of
insulin secretion by signaling via NMDA receptors. The PI will employ
a mouse insulinoma cell line, MIN6 to study binding and signaling
characteristics of endogenously expressed NMDA receptors in insulin-
secreting cells and compare those findings with observations made in
human embryonic kidney cells (HEK 293 cells) and monkey kidney COS-1
cells expressing NMDA receptors comprised of specific subunits by gene
transfer. 2) To determine which subunits form dynorphin-binding NMDA
receptors so as to begin to delineate the domain(s) on the subunit(s)
that directly bind dynorphin and related peptides. The experiments
involving expression of NMDA receptor subunits will be performed in
transfected HEK 293 cells and COS-1 cells in which the receptors can be
expressed to high levels. 3) To determine the pharmacophore within the
dynorphin peptide. That is, to determine the smallest peptide that
retains the NMDA receptor-binding and insulin secretagogue
characteristics of Dyn A(1-17). These experiments will be performed in
MIN6, HEK 293 and COS-1 cells. If the dynorphin-NMDA receptor-calcium
pathway were shown to sensitize beta cells to glucose-induced insulin
secretion, a long-term goal of this research will be to develop
nonpeptidic, orally active drugs that can be used to treat diabetes
mellitus in humans.
在这个项目中,PI提出了一系列实验来确定
强啡肽和相关多肽是否通过一种机制发挥作用
不依赖于蛋白偶联的阿片受体,与
葡萄糖刺激胰岛β细胞分泌胰岛素
朗格汉斯群岛。以下假设将得到检验。
强啡肽通过以下途径使β细胞对葡萄糖诱导的胰岛素分泌敏感
激活(或延长)N-甲基-D-天冬氨酸的激活
(NMDA)-选择性兴奋性离子型谷氨酸受体。强啡肽
A是阿片肽家族的一员,这些阿片肽似乎起作用
主要作为神经调节剂与G蛋白偶联相互作用
受体(GPCRs);Mu、kappa和NMDA受体是
一类配体门控离子通道,当被激活时,会增加
细胞表面膜对Ca~(2+)(以及Na~+和K~+)和
从而提高细胞内游离钙离子浓度。中的高程
胞浆内游离的C2+将反过来使细胞对刺激敏感
葡萄糖和情侣刺激胰岛素的分泌。
将追求的具体目标是:1)确定
强啡肽和相关多肽与葡萄糖刺激的协同作用
通过NMDA受体传递信号来分泌胰岛素。私家侦探将雇用
小鼠胰岛素瘤细胞系MIN6的结合和信号转导研究
胰岛素中内源性表达的NMDA受体的特性
并将这些发现与在
人胚胎肾细胞(HEK 293细胞)和猴肾COS-1细胞
通过基因表达由特定亚基组成的NMDA受体的细胞
调职。2)确定哪些亚基形成强啡肽结合NMDA
受体,从而开始描绘亚单位(S)上的结构域(S)
直接结合强啡肽和相关的多肽。这些实验
涉及NMDA受体亚单位的表达将在
转染HEK 293细胞和COS-1细胞
表达到高水平。3)确定体内的药效团
强啡肽。也就是说,确定最小的多肽
保留NMDA受体结合和胰岛素促分泌剂
Dyn A(1-17)的特征。这些实验将在
MIN6、HEK 293和COS-1细胞。如果强啡肽-NMDA受体-钙
途径被证明能使β细胞对葡萄糖诱导的胰岛素敏感
分泌物,这项研究的长期目标将是发展
可用于治疗糖尿病的非肽类口服活性药物
人类患上的糖尿病。
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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MARVIN C GERSHENGORN其他文献
MARVIN C GERSHENGORN的其他文献
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{{ truncateString('MARVIN C GERSHENGORN', 18)}}的其他基金
BIOLOGY OF HHV8/KSHV G PROTEIN COUPLED RECEPTOR
HHV8/KSHV G 蛋白偶联受体的生物学
- 批准号:
2653230 - 财政年份:1998
- 资助金额:
$ 17.29万 - 项目类别:
BIOLOGY OF HHV8/KSHV G PROTEIN COUPLED RECEPTOR
HHV8/KSHV G 蛋白偶联受体的生物学
- 批准号:
2882491 - 财政年份:1998
- 资助金额:
$ 17.29万 - 项目类别:
THYROTROPIN RELEASING HORMONE RECEPTOR MOLECULAR BIOLOGY
促甲状腺素释放激素受体分子生物学
- 批准号:
2824954 - 财政年份:1998
- 资助金额:
$ 17.29万 - 项目类别:
BIOLOGY OF HHV8/KSHV G PROTEIN COUPLED RECEPTOR
HHV8/KSHV G 蛋白偶联受体的生物学
- 批准号:
6164248 - 财政年份:1998
- 资助金额:
$ 17.29万 - 项目类别:
THYROTROPIN-RELEASING HORMONE RECEPTOR MOLECULAR BIOLOGY
促甲状腺激素释放激素受体分子生物学
- 批准号:
3244300 - 财政年份:1992
- 资助金额:
$ 17.29万 - 项目类别:
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