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Molecular pharmacological aspects of the neuropeptide PACAP in brain and pancreas

神经肽 PACAP 在脑和胰腺中的分子药理学方面

基本信息

批准号：
15209009
负责人：
BABA Akemichi
金额：
$ 30.7万
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：
2003
资助国家：
日本
起止时间：
2003 至 2005
项目状态：
已结题

项目摘要

PACAP is a pleiotropic neuropeptide functioning as a neurotransmitter and neurotrophic factor. The current study was aimed to investigate the (patho)physiological roles of PACAP in brain and pancreas by a pharmacological and genetic approaches, including genetically engineered mouse models of neuropsychological dysfunctions and diabetes, as well as clinical genetic investigation. The summarized results and their respective significance are as follows :1)Our recently developed PACAP-knockout mice (PACAP-KO) exhibited remarkable phenotypes including asymmetric photic response of circadian rhythm, impaired hippocampal LTP, disappearance of inflammatory and neuropathic pain, and reduced ethanol sensitivity. These results have led to a better understanding of the physiological roles and revealed some unexpected roles of endogenous PACAP in the central nervous system.2)Behavioral and pharmacological studies on PACAP-KO proposed that the serotonin 1A receptor-mediated pathways may be critical … More ly involved in the psychostimulant-elicited paradoxical anti-hyperkinetic effects, providing insights into the pathophysiology of hyperkinetic disorder such as ADHD. In addition, it was demonstrated that protective effects exerted by PACAP on ischemic neuronal death are mainly mediated by IL-6 induction, proposing a novel and potential therapeutic approach for such pathological conditions.3)Studies in transgenic overexpression of PACAP in pancreatic b-cells under streptozotocin-induced (type 1) diabetes and in KKA^y mice (a genetic model for type 2 diabetes) suggested that PACAP plays important roles in the proliferation of b-cells and the control of pathological islet hyperplasia. We have currently identified islet genes possibly involved in the control of b-cell proliferation using laser capture microdissection coupled with DNA microarray analysis.4)A Belgian group has conducted studies in two related patients with a partial trisomy 18p and revealed three copies of the PACAP gene and elevated plasma PACAP concentrations. In collaboration with this group, we proposed that PACAP might be a physiological inhibitor of platelet activation. Less

PACAP是一种多效性神经肽，具有神经递质和神经营养因子的功能。本研究旨在通过药理学和遗传学方法，包括神经心理功能障碍和糖尿病的基因工程小鼠模型，以及临床遗传学研究，探讨PACAP在脑和胰腺中的病理生理作用。结果表明：1）PACAP基因敲除小鼠（PACAP-KO）表现出明显的光反应昼夜节律不对称、海马LTP受损、炎性疼痛和神经病理性疼痛消失、乙醇敏感性降低等表型。这些结果使我们对内源性PACAP在中枢神经系统中的生理作用有了更好的理解，并揭示了一些意想不到的作用。2）对PACAP-KO的行为学和药理学研究表明，5-羟色胺1A受体介导的途径可能是关键的 ...更多信息参与精神兴奋剂引起的矛盾的抗多动作用，提供了对多动症等多动障碍的病理生理学的见解。此外，研究表明PACAP对缺血性神经元死亡的保护作用主要通过IL-6诱导介导，3）在链脲佐菌素诱导的（1型）糖尿病下胰腺b细胞和KKA^y小鼠中PACAP转基因过表达的研究（2型糖尿病的遗传模型）表明PACAP在B细胞增殖和控制病理性胰岛增生中起重要作用。目前，我们已经确定了胰岛基因可能参与控制b细胞增殖的激光捕获显微切割结合DNA微阵列分析。4）比利时的一个小组进行了研究，在两个相关的患者与部分三体18 p和揭示三个副本的PACAP基因和血浆PACAP浓度升高。与该小组合作，我们提出PACAP可能是血小板活化的生理抑制剂。少