The functional role of Nardilysin in pancreatitis and pancreatic ductal adenocarcinoma formation

2018 Fiscal Year Final Research Report

• Project/Area Number: 17H06804
• Research Category: Grant-in-Aid for Research Activity Start-up
• Allocation Type: Single-year Grants
• Research Field: Gastroenterology
• Research Institution: Kyoto University
• Principal Investigator: Ikuta Kozo 京都大学, 医学研究科, 客員研究員 (60802741)
• Project Period (FY): 2017-08-25 – 2019-03-31
• Keywords: 膵炎 / 膵癌

Outline of Final Research Achievements

Nardilysin (NRDC), a zinc peptidase, exhibits multiple localisation-dependent functions. We found that pancreatic deletion of Nrdc leads to spontaneous chronic pancreatitis concomitant with acinar-to-ductal conversion, increased apoptosis and atrophic pancreas in mice. Acinar-to-ductal conversion was observed mainly through a non-cell autonomous mechanism, and the expression of several chemokines was significantly increased in Nrdc-null pancreatic acinar cells. Furthermore, pancreatic deletion of Nrdc dramatically accelerated KrasG12D-driven PanIN and subsequent PDA formation in mice. These data demonstrate a previously unappreciated antiinflammatory and tumour suppressive functions of Nrdc in the pancreas in mice. Finally, absence of NRDC expression was observed in a subset of human PanIN and PDA.

Free Research Field

消化器内科

Academic Significance and Societal Importance of the Research Achievements

膵炎の一種である遺伝性膵炎は難治性であり、遺伝性膵炎患者は膵癌を発症する確率が非常に高い。また、遺伝性膵炎患者のおよそ30%で、原因遺伝子が解明されていない。そのため、遺伝性膵炎の新規治療法の発見や発生メカニズムの解明が急務である。当研究で、マウスにおいて、膵のナルディライジンが、膵炎発症、膵腫瘍発生に抑制的に働くことが明らかになり、ヒト膵癌の一部でナルディライジンが欠失していた。このことから、ナルディライジンは、遺伝性膵炎およびそれに付随する膵癌治療の新たなターゲットとなる可能性が示唆された。