HPA軸における循環血液中microRNAの生理的・病理的意義の解明

2022 Fiscal Year Annual Research Report

• Project/Area Number: 20K08907
• Research Institution: Kobe University
• Principal Investigator: 山本 雅昭 神戸大学, 医学研究科, 助教 (30724017)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Keywords: 神経内分泌学 / エクソソーム / バイオマーカー / メタボローム / miRNA

Outline of Annual Research Achievements

本研究ではコルチゾール不足の影響を検討するために、副腎不全のモデルとしてACTH値が測定感度未満で、かつ尿中遊離コルチゾール値が測定感度未満であるACTH単独欠損症(IAD)重症群2名およびACTH、尿中遊離コルチゾール値が中等度低下している中等症群2名ですでに生理量のステロイド補充としてヒドロコルチゾン(HC)内服している患者計4名を対象とした。HC最終内服から24時間後を基礎値(IN)、72時間後を副腎不全状態(OFF)と仮定し血液を採取した。その検体を用いてIAD診断バイオマーカーの探索を行った。
①エクソソーム内miRNA発現量解析 IAD患者におけるIN/OFFでの血清エクソソーム中のmiRNA発現を検討するために、超遠心法を用いてエクソソームの単離を行い、ナノサイトによる粒子径計測およびウエスタンブロット法によりCD-9、CD-63、ALIX発現を同定し、抽出された粒子がエクソソームであることを確認した。その検体をmiRNA-seqで解析し、副腎不全状態で有意に変化するmiRNA群を20種類程度得ることができた。
②血液中mRNA発現量解析 IAD患者におけるIN/OFFでの全血液からmRNAを抽出しRNA-seqを行いINとOFFの発現量を比較すると53の遺伝子で有意な変化を認めた。そのうち重症群で有意差を認めた19遺伝子に対してqPCRで発現量が豊富で安定な定量性が確認できた3種類の遺伝子(A、B、C)を候補として同定した。
③血清メタボローム解析 本学質量分析総合センターとの共同研究によりIAD患者におけるIN/OFFでの血清中代謝産物の変化を検討したところOFFの状態ではINの状態と比較して7種類の代謝産物が有意に減少していることが明らかとなった。
①～③の成果で得られたバイオマーカーが臨床応用可能かを今後の検討課題とする。

Research Products

• [Journal Article] Survey of glucocorticoid dose escalation in patients with adrenal insufficiency during the peri-COVID-19 vaccination period. (2023)
  • Author(s): Hironori Bando, Masaaki Yamamoto, Michiko Takahashi, Keitaro Kanie, Yuriko Sasaki, Yuka Oi, Seiji Tomofuji, Kaori Hozumi, Seiji Nishikage, Shin Urai, Naoki Yamamoto, Masaki Suzuki, Hiroki Shichi, Genzo Iguchi, Hidenori Fukuoka, Wataru Ogawa
  • Journal Title: Endocrine Journal Volume: 70 Pages: 89~95
  • DOI: 10.1507/endocrj.EJ22-0390.
  • Peer Reviewed / Open Access
• [Journal Article] Novel genes and variants associated with congenital pituitary hormone deficiency in the era of next-generation sequencing (2023)
  • Author(s): Hironori Bando, Shin Urai, Keitaro Kanie, Yuriko Sasaki, Masaaki Yamamoto, Hidenori Fukuoka, Genzo Iguchi, Sally A Camper
  • Journal Title: Front Endocrinol (Lausanne) Volume: 13 Pages: 1008306
  • DOI: 10.3389/fendo.2022.1008306.
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] High Cortisol Concentration Without Cushingoid Appearance. (2023)
  • Author(s): Hironori Bando, Keitaro Kanie, Masaaki Yamamoto, Hidenori Fukuoka
  • Journal Title: Am J Med. Volume: 136 Pages: e43-e44
  • DOI: 10.1016/j.amjmed.2022.10.009.
  • Peer Reviewed / Open Access
• [Journal Article] Successful diagnosis and treatment of pheochromocytoma during severe coronavirus disease 2019 (COVID-19): a case report. (2023)
  • Author(s): Yasutaka Tsujimoto, Masaaki Yamamoto, Seiji Nishikage, Keitaro Kanie, Maki Kanzawa, Hironori Bando, Kei Yoshino, Yushi Hirota, Hidenori Fukuoka, Wataru Ogawa
  • Journal Title: Endocrine Journal Volume: 70 Pages: 259-265.
  • DOI: 10.1507/endocrj.EJ22-0446
  • Peer Reviewed / Open Access
• [Journal Article] Combined Hypophysitis and Type 1 Diabetes Mellitus Related to Immune Checkpoint Inhibitors. (2023)
  • Author(s): Yasunori Fujita, Fumika Kamitani, Masaaki Yamamoto, Hidenori Fukuoka,Yushi Hirota, Nobuharu Nishiyama, Naho Goda, Yuko Okada, Yuiko Inaba, Keitaro Kanie, Hiroki Shichi, Shin Urai, Masaki Suzuki, Naoki Yamamoto, Hironori Bando, Genzo Iguchi, Yutaka Takahashi, Wataru Ogawa
  • Journal Title: J Endocr Soc. Volume: 7 Pages: bvad002
  • DOI: 10.1210/jendso/bvad002.
  • Peer Reviewed / Open Access
• [Journal Article] The Impact of Multicultural Interfacility Video Case Conference: A Novel Education Model After the COVID Pandemic. (2023)
  • Author(s): Takako Araki, Hiraku Kameda, Masaaki Yamamoto, Toru Tateno, Yasumasa Iwasaki, Run Yu, Constance Chik, Hiba Hashmi, Angela Radulescu, Lynn A Burmeister, Hidenori Fukuoka
  • Journal Title: J Endocr Soc. Volume: 7 Pages: bvad023.
  • DOI: 10.1210/jendso/bvad023.
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Coexistence of growth hormone, adrenocorticotropic hormone, and testosterone deficiency associated with coronavirus disease 2019: a case followed up for 15 months. (2022)
  • Author(s): Kai Yoshimura, Masaaki Yamamoto, Tomoya Inoue, Hidenori Fukuoka, Keiji Iida, Wataru Ogawa
  • Journal Title: Endocrine Journal Volume: 69 Pages: 1335-1342
  • DOI: 10.1507/endocrj.EJ22-0108.
  • Peer Reviewed / Open Access
• [Journal Article] Genetic and Epigenetic Pathogenesis of Acromegaly (2022)
  • Author(s): Masaaki Yamamoto, Yutaka Takahashi
  • Journal Title: Cancers (Basel) Volume: 14 Pages: 3861
  • DOI: 10.3390/cancers14163861.
  • Peer Reviewed / Open Access
• [Journal Article] Responsiveness to DDAVP in Cushing's disease is associated with USP8 mutations through enhancing AVPR1B promoter activity. (2022)
  • Author(s): Hiroki Shichi, Hidenori Fukuoka, Maki Kanzawa, Masaaki Yamamoto, Naoki Yamamoto, Masaki Suzuki, Shin Urai, Ryusaku Matsumoto, Keitaro Kanie, Yasunori Fujita, Hironori Bando, Genzo Iguchi, Naoko Inoshita, Shozo Yamada, Yutaka Takahashi, Wataru Ogawa
  • Journal Title: Pituitary Volume: 25 Pages: 496-507.
  • DOI: 10.1007/s11102-022-01220-4.
  • Peer Reviewed
• [Journal Article] Relation between the insulin lowering rate and changes in bone mineral density: Analysis among subtypes of type 1 diabetes mellitus. (2022)
  • Author(s): Masaki Suzuki, Shin Urai, Hidenori Fukuoka, Yushi Hirota, Masaaki Yamamoto, Yuko Okada, Naoki Yamamoto, Hiroki Shichi, Yasunori Fujita, Keitaro Kanie, Genzo Iguchi, Yutaka Takahashi, Wataru Ogawa
  • Journal Title: Journal of Diabetes Investigation Volume: 13 Pages: 1585-1595.
  • DOI: 10.1111/jdi.13817.
  • Peer Reviewed / Open Access
• [Journal Article] Bilateral adrenal uptake of 123I MIBG scintigraphy with mild catecholamine elevation, the diagnostic dilemma, and its characteristics (2022)
  • Author(s): Yuiko Inaba, Masaaki Yamamoto, Shin Urai, Masaki Suzuki, Seiji Nishikage, Maki Kanzawa, Yayoi Aoyama, Tomonori Kanda, Katsumi Shigemura, Hironori Bando, Genzo Iguchi, Yasuhiro Nakamura, Masato Fujisawa, Akihisa Imagawa, Hidenori Fukuoka, Wataru Ogawa
  • Journal Title: Scientific Reports Volume: 12 Pages: 9276
  • DOI: 10.1038/s41598-022-13132-1.
  • Peer Reviewed / Open Access
• [Journal Article] The Effect of Aging on Quality of Life in Acromegaly Patients Under Treatment (2022)
  • Author(s): Naoki Yamamoto, Shin Urai, Hidenori Fukuoka, Masaaki Yamamoto, Kenichi Yoshida, Masaki Suzuki, Hiroki Shichi, Yasunori Fujita, Keitaro Kanie, Genzo Iguchi, Yutaka Takahashi, Wataru Ogawa
  • Journal Title: Front Endocrinol (Lausanne). Volume: 13 Pages: 819330
  • DOI: 10.3389/fendo.2022.819330.
  • Peer Reviewed / Open Access
• [Presentation] 下垂体疾患の病因・病態の解明 (2022)
  • Author(s): 山本雅昭
  • Organizer: 第95回日本内分泌学会学術総会
  • Invited
• [Book] The Pituitary 5th Edition. Chapter 11: Pituitary-Immune Interface (2022)
  • Author(s): Masaaki Yamamoto, Yutaka Takahashi
  • Total Pages: 790
  • Publisher: Elsevier
  • ISBN: 9780323998994
• [Book] 薬剤性内分泌障害診療マニュアル (2022)
  • Author(s): 山本雅昭
  • Total Pages: 132
  • Publisher: 診断と治療社
  • ISBN: 9784787824936