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Study on the possibility for drug utilization of peptidergic neurotransmitter using knockout mouse

利用基因敲除小鼠研究肽能神经递质药物利用的可能性

基本信息

批准号：
07557157
负责人：
BABA Akemichi
金额：
$ 10.75万
依托单位：
Osaka University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (A)
财政年份：
1995
资助国家：
日本
起止时间：
1995 至 1997
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-07557157/
关键词：
VIP PACAP Receptor Knockout mouse Gane targeting Neurotransmitter peptide マウス幹細胞

项目摘要

PACAP has an amino acid sequence identity of 68% with vasoactive intestinal polypeptide (VIP) and regulates a wide range of physiological functions in the central and peripheral nervous systems. Three genes encoding PACAP/VIP receptor subtypes, which bind PACAP with a high affinity, have been cloned, but the physiological significance of each subtype has not been completely characterized. To elucidate the role of the PACAP signaling system, we have used gene targeting in embryonic stem cells to disrupt exon 2 of the PACAP receptor gene, and characterized the mutant mice as well as wildtype mice.1. The mutant mice had reduced [^<125>I]PACAP-27 binding and cAMP production in their brains.2. The mutant mice, however, were viable and fertile, and morphologically, histologically and electrophysiologically indistinguishable from their wild-type counterparts.3. Coexpression of PACAP receptor and PACAP was seen in the sympathetic nervous system of the wild-type mice and rats.4. In the sympathetic neurons, PACAP stimulates the expression of PACAP receptor and PACAP mRNAs at a transcriptional level.5. The mechanism of the PACAP production was studied in mouse insulinoma cells.In conclusion, these results suggest that PACAP acts as a autocrine or paracrine regulatory factor and contributes to sustained activation of the sympathoadrenal system, and that PACAP regulates glucose-stimulated insulin secretion from beta cells by an autocrine mechanism. However, the intact PACAP receptor is not a prerequisite for normal mouse development of for survival.

PACAP 与血管活性肠多肽 (VIP) 的氨基酸序列同一性为 68%，可调节中枢和周围神经系统的广泛生理功能。编码 PACAP/VIP 受体亚型的三个基因已被克隆，它们以高亲和力结合 PACAP，但每种亚型的生理意义尚未完全表征。为了阐明PACAP信号系统的作用，我们在胚胎干细胞中使用基因打靶来破坏PACAP受体基因的外显子2，并对突变小鼠和野生型小鼠进行了表征。1．突变小鼠大脑中的[^ 125 I]PACAP-27结合和cAMP产生减少。2．然而，突变小鼠具有存活能力和生育能力，并且在形态学、组织学和电生理学上与野生型小鼠没有区别。3． PACAP受体与PACAP在野生型小鼠和大鼠的交感神经系统中共表达。 4．在交感神经元中，PACAP在转录水平刺激PACAP受体和PACAP mRNA的表达。5．在小鼠胰岛素瘤细胞中研究了 PACAP 产生的机制。总之，这些结果表明 PACAP 作为自分泌或旁分泌调节因子，有助于交感肾上腺系统的持续激活，并且 PACAP 通过自分泌机制调节葡萄糖刺激的 β 细胞胰岛素分泌。然而，完整的 PACAP 受体并不是小鼠正常发育或生存的先决条件。