2018 Fiscal Year Final Research Report

Elucidation of regulation mechanism for neuropeptide signaling in the pathogenesis of inflammatory bowel diseases and its application to the therapy

Research Project

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Project/Area Number	16H05409
Research Category	Grant-in-Aid for Scientific Research (B)
Allocation Type	Single-year Grants
Section	一般
Research Field	Digestive surgery
Research Institution	Hokkaido University
Principal Investigator	Taketomi Akinobu 北海道大学, 医学研究院, 教授 (70363364)
Co-Investigator(Kenkyū-buntansha)	高橋典彦北海道大学, 大学病院, 准教授 (30399894) 本間重紀北海道大学, 医学研究院, 講師 (30533674) 北村秀光北海道大学, 遺伝子病制御研究所, 准教授 (40360531) 谷野美智枝旭川医科大学, 病院病理部, 教授 (90360908)
Project Period (FY)	2016-04-01 – 2019-03-31
Keywords	炎症性腸疾患 / 潰瘍性大腸炎 / クローン病 / 神経ペプチド / 神経ペプチド受容体 / STAT1 / マクロファージ / 樹状細胞
Outline of Final Research Achievements	In this study, we investigated the precise roles of STAT1 and neuropeptide signaling through NK2R, a receptor of neurokinin A, in inflammatory bowel disease (IBD) involving with inflammation and immune responses by using a dextran sulfate sodium (DSS)-induced colitis model and in vitro experiments. We found that NK2R expression levels of macrophages and dendritic cells were augmented by type-1 IFN stimulations and involved in the inflammation and immune responses in a STAT-1-dependent manner. Next, we revealed that STAT1-mediated induction of a chemokine and its receptor were related to disease state of DSS-induced colitis model. Furthermore, we confirmed STAT1 activation and NK2R expression in lesion and inflammation areas of patients with IBD such as ulcerative colitis and Crohn’s diseases. Based on these findings we speculate that regulation of STAT1 and neuropeptide signaling and the downstream molecules may be a promising strategy in the development of effective therapy for IBD.
Free Research Field	炎症性腸疾患、消化器外科
Academic Significance and Societal Importance of the Research Achievements	先進国・日本において潰瘍性大腸炎、クローン病などの難治性・慢性炎症性腸疾患が年々増加している。抗炎症・免疫抑制剤により患者のQOLが以前よりは改善されたものの、病態の改善・治療のための基礎・臨床研究は依然として重要である。本研究は、病態の重篤化の新たな要因を見出したことに意義がある。今後、STAT1の活性とその下流標的分子の制御が難治性炎症性腸疾患の治療法としてさらに精査されることが望まれる。単一の治療法で強い効果が得られなくても、治療法の選択肢が増えれば、併用による相乗効果等も期待される。