2005 Fiscal Year Final Research Report Summary
Molecular pharmacological aspects of the neuropeptide PACAP in brain and pancreas
| Project/Area Number |
15209009
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| Research Category |
Grant-in-Aid for Scientific Research (A)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
General pharmacology
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| Research Institution | Osaka University |
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Principal Investigator |
BABA Akemichi Osaka Univ, Grad Sch of Pharmaceutic Sci, Prof, 薬学研究科, 教授 (70107100)
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| Co-Investigator(Kenkyū-buntansha) |
MATSUDA Toshio Osaka Univ, Grad Sch of Pharmaceutic Sci, Prof, 薬学研究科, 教授 (00107103)
HASHIMOTO Hitoshi Osaka Univ, Grad Sch of Pharmaceutic Sci, Assoc Prof, 薬学研究科, 助教授 (30240849)
SHINTANI Norihito Osaka Univ, Grad Sch of Pharmaceutic Sci, Res Assoc, 薬学研究科, 助手 (10335367)
SHIODA Seiji Showa Univ, Dep Med, Prof, 医学部, 教授 (80102375)
YADA Toshihiko Jichi Medical Sch, Dep Med, Prof, 医学部, 教授 (60166527)
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| Project Period (FY) |
2003 – 2005
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| Keywords | PACAP / gene-modified mice / mental disease / ADHD / IL-6 / diabetes mellitus / b-cell / linkage analysis |
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| Research Abstract |
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
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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
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