The role of endoplasmic reticulum stress in endocrinopathy associated with IgG4 related disease

• Project/Area Number: 20K17518
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 54040:Metabolism and endocrinology-related
• Research Institution: Wakayama Medical University
• Principal Investigator: Takeshima Ken 和歌山県立医科大学, 医学部, 講師 (40647517)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000); Fiscal Year 2022: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2021: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2020: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
• Keywords: IgG4関連疾患 / IgG4-RD / 小胞体ストレス / キナーゼ阻害薬 / ＩｇＧ４関連疾患 / 内分泌 / 膵 / 甲状腺

Outline of Research at the Start

本研究では、IgG4 関連疾患患者におけるステロイド治療前後の内分泌機能、関連臓器病変の組織における小胞体ストレスを評価し、①内分泌異常を伴う IgG4関連疾患の病態における小胞体ストレスの役割、②小胞体ストレスがステロイド治療後の内分泌機能に与える影響を検討する。加えて、③内分泌臓器病変を合併した IgG4 関連疾患モデルマウスの作成を試み、④小胞体ストレスを減弱させるキナーゼ阻害薬（KIRA）が内分泌機能異常を改善するかを明らかにすることを目的とする。

Outline of Final Research Achievements

In this research, we attempted to develop an animal model of IgG4-related disease and to clarify the role of endoplasmic reticulum stress in endocrinopathy associated with IgG4 related disease.
We firstly injected serum IgGs from patients with IgG4-related disease to neonatal mice　and evaluated pathological features of the pancreas; deposition of IgG4 antibodies at the interstitial area between pacreatic acinar cells.
We also immunized Laminin511, a potential corresponding antigen of IgG4 antibodies, with BALB/C mice and evaluated the glucose tolerance. IPGTT revelaed that the serum glucose levels are higher in Laminin 511 group than in control group after 15 minites of glucose stimulation, but not significantly. In addition, mRNA expressions associated with endoplasmic reticulum stress showed no differences between the groups.

Academic Significance and Societal Importance of the Research Achievements

本研究は、IgG4関連疾患モデルマウスの作成を試み、未だ検討が行われていない IgG4 関連疾患に伴う内分泌異常と小胞体ストレスの関連性に着目した点で意義がある。本研究で患者血清由来IgGsおよびLaminin511を用いたIgG4関連疾患モデルマウスでは、十分な炎症細胞浸潤と小胞体ストレスの亢進が認められなかった。しかし、今後小胞体ストレス亢進を伴うモデルマウスを作成できれば、小胞体ストレスを減弱するKIRAが新たな治療選択となりうるため、将来的に新たな治療法への応用につながる可能性があり、この点において意義がある。

Research Products

• [Journal Article] Nobuyuki Nishi, Ken Takeshima, Shuhei Morita, Hiroshi Iwakura, Masahiro Nishi, Takaaki Matsuoka (2021)
  • Author(s): Nobuyuki Nishi, Ken Takeshima, Shuhei Morita, Hiroshi Iwakura, Masahiro Nishi, Takaaki Matsuoka
  • Journal Title: Endocrinol Diabetes Metab Case Rep Volume: 2021 Pages: 21-0029
  • DOI: 10.1530/edm-21-0029
  • Peer Reviewed / Open Access
• [Journal Article] Proposal of diagnostic criteria for IgG4-related thyroid disease (2021)
  • Author(s): Takeshima Ken、Li Yaqiong、Kakudo Kennichi、Hirokawa Mitsuyoshi、Nishihara Eijun、Shimatsu Akira、Takahashi Yutaka、Akamizu Takashi
  • Journal Title: Endocrine Journal Volume: 68 Issue: 1 Pages: 1-6
  • DOI: 10.1507/endocrj.EJ20-0557
  • NAID: 130007975890
  • ISSN: 0918-8959, 1348-4540
  • Peer Reviewed / Open Access
• [Journal Article] Expression of unfolded protein response markers in the pheochromocytoma with Waardenburg syndrome: a case report (2020)
  • Author(s): Morita Shuhei、Takeshima Ken、Ariyasu Hiroyuki、Furukawa Yasushi、Kishimoto Shohei、Tsuji Tomoya、Uraki Shinsuke、Mishima Hiroyuki、Kinoshita Akira、Takahashi Yuichi、Inaba Hidefumi、Iwakura Hiroshi、Furuta Hiroto、Nishi Masahiro、Doi Asako、Murata Shin-ichi、Yoshiura Koh-ichiro、Akamizu Takashi
  • Journal Title: BMC Endocrine Disorders Volume: 20 Issue: 1 Pages: 90-90
  • DOI: 10.1186/s12902-020-00574-9
  • Peer Reviewed / Open Access
• [Book] 胆と膵 (2022)
  • Author(s): 竹島 健, 赤水 尚史
  • Total Pages: 302
  • Publisher: 医学図書出版
  • ISBN: 9784865174984