Role of pancreatic retinoid storage in pancreatic fibrosis and carcinogenesis

• Project/Area Number: 19K17396
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 53010:Gastroenterology-related
• Research Institution: Gifu University
• Principal Investigator: Ozawa Noritaka 岐阜大学, 大学院医学系研究科, 招へい教員 (60761450)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2021: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2019: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000)
• Keywords: 膵癌 / 膵線維化 / レチノイド / 膵星細胞 / 慢性膵炎 / レチノイド(ビタミンA)

Outline of Research at the Start

慢性膵炎や膵癌において病態進展の中心的役割を果たす膵星細胞は、活性化に伴いレチノイド (ビタミンA)を含む脂肪滴を失う。しかし、膵貯蔵レチノイドが膵臓の病態に及ぼす影響については十分に解明されていない。
本研究において、遺伝子改変マウスを用い下記を目的として実験を行う。
・レチニルエステル合成酵素欠損マウスの、膵レチノイド欠如モデルとしての有用性を検証する。
・膵線維化・膵発癌過程における膵星細胞活性化と、脂肪滴喪失の関連性について解明し、膵貯蔵レチノイドの役割を明らかにする。

Outline of Final Research Achievements

The roles of retinoid storage in pancreatic stellate cells on pancreatic cancer and fibrosis were investigated. In lecithin:retinol acyltransferase (LRAT)-deficient mice, pancreatic retinoid storage measured by HPLC were significantly decreased compared to the control. In a model of pancreatitis and pancreatic fibrosis induced by caerulein injections, serum amylase and lipase were significantly higher and the mRNA expression level of fibrosis marker Timp1 was markedly elevated in the pancreas of LRAT-deficient mice. In addition, the pancreatic histology in mutant mice showed exacerbation of pancreatitis and significant increase of fibrous tissue. These results indicated LRAT deficiency exacerbates chronic pancreatitis and fibrosis, suggesting that differences in retinoid levels in pancreatic tissue might affect the pathology of the pancreas.

Academic Significance and Societal Importance of the Research Achievements

レチニルエステル合成酵素(LRAT)欠損マウスの膵貯蔵レチノイドは有意に低値であったことから、この遺伝子改変マウスが膵レチノイド貯蔵欠如モデルとして適切であることが見出された。また、膵線維化モデルを用いた実験結果から、LRAT欠損すなわち膵レチノイド貯蔵の減少により慢性膵炎、膵線維化が増悪することが示された。
本研究結果は、膵貯蔵レチノイドが慢性膵炎および膵線維化を抑制する可能性を示しており、膵星細胞へのレチノイド補充もしくは脂肪滴喪失の阻害による、慢性膵炎・膵線維化および膵癌に対する治療法の開発につながると考えられる。

Research Products

• [Journal Article] 早期胃癌研究会症例 腸上皮化生領域と完全一致した胃神経内分泌腫瘍の1例 (2021)
  • Author(s): 山崎 健路、岩田 圭介、清水 省吾、清水 雅仁、九嶋 亮治、谷口 裕紀、吉田 泰之、吉田 健作、小澤 範高、長谷川 恒輔、丸田 明範、永野 淳二
  • Journal Title: 胃と腸 Volume: 56 Issue: 3 Pages: 371-377
  • DOI: 10.11477/mf.1403202287
  • ISSN: 0536-2180, 1882-1219
  • Year and Date: 2021-03-25
  • Peer Reviewed
• [Journal Article] Graft‐versus‐host disease‐like reactions in the gastrointestinal tract in a patient with SARS‐CoV‐2 infection (2021)
  • Author(s): Ozawa Noritaka、Yamazaki Kenji、Kushima Ryoji
  • Journal Title: Digestive Endoscopy Volume: 33 Issue: 5 Pages: 876-877
  • DOI: 10.1111/den.13994
  • Peer Reviewed / Open Access
• [Journal Article] Inhibitory effects of a selective prostaglandin E2 receptor antagonist RQ-15986 on inflammation-related colon tumorigenesis in APC-mutant rats (2021)
  • Author(s): Shirakami Yohei、Nakanishi Takayuki、Ozawa Noritaka、Ideta Takayasu、Kochi Takahiro、Kubota Masaya、Sakai Hiroyasu、Ibuka Takashi、Tanaka Takuji、Shimizu Masahito
  • Journal Title: PLOS ONE Volume: 16 Issue: 5 Pages: e0251942-e0251942
  • DOI: 10.1371/journal.pone.0251942
  • Peer Reviewed / Open Access
• [Journal Article] Olmesartan-associated sprue-like enteropathy diagnosed by capsule endoscopy and double balloon endoscopy (2021)
  • Author(s): Taguchi Daisuke、Ibuka Takashi、Arao Masamichi、Mizutani Taku、Ozawa Noritaka、Kubota Masaya、Shirakami Yohei、Shiraki Makoto、Araki Hiroshi、Shimizu Masahito
  • Journal Title: Clinical Journal of Gastroenterology Volume: 14 Issue: 6 Pages: 1649-1654
  • DOI: 10.1007/s12328-021-01514-3
  • Peer Reviewed / Open Access
• [Journal Article] Idiopathic Ileocolonic Varices Coexisting with a Colon Polyp Treated Successfully by Endoscopy: A Case Report and Literature Review (2019)
  • Author(s): Miwa T, Ibuka T, Ozawa N, Sugiyama T, Kubota M, Imai K, Sakai H, Takai K, Araki H, Shimizu M.
  • Journal Title: Internal Medicine Volume: 58 Issue: 23 Pages: 3401-3407
  • DOI: 10.2169/internalmedicine.3131-19
  • NAID: 130007754641
  • ISSN: 0918-2918, 1349-7235
  • Year and Date: 2019-12-01
  • Peer Reviewed / Open Access
• [Journal Article] Effective Treatment of Cytotoxic Agent Refractory Alpha-Fetoprotein-Producing Gastric Cancer with Ramucirumab: a Case Report and Review of the Literature. (2019)
  • Author(s): Takada J, Araki H, Ozawa N, Sugiyama T, Kubota M, Ibuka T, Shimizu M.
  • Journal Title: J Gastrointest Cancer. Volume: 50 Issue: 3 Pages: 556-559
  • DOI: 10.1007/s12029-017-0043-6
  • Peer Reviewed / Open Access
• [Journal Article] Acute cytomegalovirus infection in an immunocompetent patient with ulcerative colitis: A case report. (2019)
  • Author(s): Maeda T, Sakai H, Ozawa N, Sugiyama T, Takada J, Kubota M, Ibuka T, Shirakami Y, Araki H, Shimizu M.
  • Journal Title: Exp Ther Med. Volume: 18 Pages: 2271-2277
  • DOI: 10.3892/etm.2019.7823
  • Peer Reviewed / Open Access
• [Journal Article] Safety of Carbon Dioxide Insufflation during Endoscopic Submucosal Dissection for Esophageal Squamous Cell Carcinoma (2018)
  • Author(s): Takada Jun、Araki Hiroshi、Mizutani Taku、Ozawa Noritaka、Sugiyama Tomohiko、Kubota Masaya、Ibuka Takashi、Shimizu Masahito
  • Journal Title: Digestive Diseases Volume: 37 Issue: 2 Pages: 93-99
  • DOI: 10.1159/000492870
  • Peer Reviewed / Open Access
• [Presentation] COVID-19流行下のIBD診療における便中カルプロテクチンの有用性の検討 (2021)
  • Author(s): 小澤範高, 山崎健路, 大谷毅一, 林冴加, 廣田大輝, 増田直也, 谷口裕紀, 嶋田貴仁, 吉田健作, 長谷川恒輔, 丸田明範, 永野淳二, 岩田圭介, 清水省吾
  • Organizer: 第63回日本消化器病学会大会
• [Presentation] IBDおよびIBS診療における便中カルプロテクチンの有用性の検討 (2021)
  • Author(s): 小澤 範高, 山崎 健路, 大谷 毅一, 林 冴加, 廣田 大輝, 増田 直也, 谷口 裕紀, 嶋田 貴仁, 吉田 健作, 長谷川 恒輔, 丸田 明範, 永野 淳二, 岩田 圭介, 清水 省吾
  • Organizer: 第101回日本消化器内視鏡学会総会