臨床化学的手法を基盤とする先天性胆汁酸代謝異常症の病態解析

• Project/Area Number: 15K01809
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Biomolecular chemistry
• Research Institution: Nihon University
• Principal Investigator: 飯田 隆 日本大学, 文理学部, 教授 (60060125)
• Project Period (FY): 2015-04-01 – 2017-03-31
• Project Status: Discontinued (Fiscal Year 2016)
• Budget Amount: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000); Fiscal Year 2017: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2016: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2015: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: 造血幹細胞 / 胆汁酸 / 二次胆汁酸 / 液体クロマトグラフータンデム質量分析 / IEBAM疾患 / NPDC疾患 / LC-MS/MS / 異常胆汁酸 / 多重抱合体

Outline of Annual Research Achievements

全ての血液細胞の源である造血幹細胞は、大人の体内では骨髄の内部で休眠状態にあるが、発生中の胎児では肝臓（胎児肝）で活発に増殖している。造血幹細胞はストレスに弱く、体外で増殖させるとすぐに機能が低下してしまうことが知られているため、胎児肝の中ではどうして増殖が可能であるのか謎のままであった。当研究グループは以前、造血幹細胞はタンパク質を正常に折りたたむ能力が低いため、体外培養すると異常なタンパクが蓄積して死んでしまうことを発見していた。今回、申請者らは胎児肝では食物の消化に使われる胆汁の主成分である“胆汁酸”が異常タンパク質の蓄積を防いでいることを明らかにした。胎児肝の胆汁酸が減少するマウスを解析したところ、増殖するはずの造血幹細胞が大幅に減少していることが判明した。これらの発見は、白血病治療などに対する骨髄・臍帯血移植技術の改良に繋がるだけでなく、妊娠期に胎児に起こる疾病の解明など貢献するものと期待される。

Research Products

• [Journal Article] 3,4-Seco-12α-hydroxy-5β-cholan-3,4,24-trioic acid, a novel secondary bile acid: isolation from the bile of the common ringtail possum (Preudocheirus peregrinus) and chemical synthesis. (2017)
  • Author(s): S.Sekiguchi, K.Namegawa, N.Nakane, R.Satoh, K.Omura, L.R.Hagey, A.F.Hofmann, T.Iida.
  • Journal Title: J. Pharmacogn. Nat. Prod. Volume: 3 Issue: 01 Pages: 1000131-1000131
  • DOI: 10.4172/2472-0992.1000131
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] 2.Novel, major 2α- and 2β-hydroxy bile alcohols and bile acids in the bile of Arapaima gigas, a large South American river fish. (2016)
  • Author(s): Sato Née Okihara R, Saito T, Ogata H, Nakane N, Namegawa K, Sekiguchi S, Omura K, Kurabuchi S, Mitamura K, Ikegawa S, Raines J, Hagey LR, Hofmann AF, Iida T.
  • Journal Title: Steroids Volume: 107 Pages: 112-120
  • DOI: 10.1016/j.steroids.2016.01.001
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Bile Acids Protect Expanding Hematopoietic Stem Cells from Unfolded Protein Stress in Fetal Liver (2016)
  • Author(s): V.Sigurdsson, H.Takei, S.Sobeleva, V.Radulovic, R.Galeev, K.Siva, L.M.F.Leeb-Lundberg, T.Iida, H.Nittono, K.Miharada.
  • Journal Title: Cell Stem Cell Volume: 18 Issue: 4 Pages: 522-532
  • DOI: 10.1016/j.stem.2016.01.002
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Two Major Bile Acids in the Hornbills, (24R,25S)-3α,7α,24-Trihydroxy-5β-cholestan-27-oyl Taurine and Its 12α-Hydroxy Derivative (2016)
  • Author(s): R.Satoh, H.Ogata, T.Saito, B.Zhou, K.Omura, S.Kurabuchi, K.Mitamura, S.Ikegawa, L.R.Hagey, A.F.Hofmann, T.Iida.
  • Journal Title: Lipids Volume: 51 Issue: 6 Pages: 757-768
  • DOI: 10.1007/s11745-016-4150-0
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Identification of novel bile acids as biomarkers for the early diagnosis of Niemann‐Pick C disease (2016)
  • Author(s): F.Mazzacuva, P.Mills, K.Mills, S.Camuzeaux, P.Gissen, E-R Nicoli, C.Wassif, D.Vruchte, F.D.Porter, M.Maekawa, N.Mano, T.Iida, F.Platt, P.T.Clayton.
  • Journal Title: FEBS Letters Volume: 590 Issue: 11 Pages: 1651-1662
  • DOI: 10.1002/1873-3468.12196
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Rifaximin Exerts Beneficial Effects Independent of its Ability to Alter Microbiota Composition (2016)
  • Author(s): D.J.Kang, G.Kakiyama, N.S.Betrapally, J.Herzog, H.Nittono, P.B.Hylemon, H.Zhou, I.Carroll, J.Yang, P.M.Gillevet, C.Jiao, H.Takei, W.H.Pandak, T.Iida, D.M.Heuman, S.Fan, O.Fiehn, T.Kurosawa, M.Sikaroodi, R.B.Sartor, J.S.Bajaj.
  • Journal Title: Clinical and Translational Gastroenterology Volume: 7 Issue: 8 Pages: e187-e187
  • DOI: 10.1038/ctg.2016.44
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Chemical Synthesis of Uncommon Natural Bile Acids: The 9α-Hydroxy Derivatives of Chenodeoxycholic and Lithocholic Acids (2016)
  • Author(s): T.Iida, K.Namegawa, N.Nakane, K.Iida, A.F.Hofmann, K.Omura.
  • Journal Title: Chemical and Pharmaceutical Bulletin Volume: 64 Issue: 9 Pages: 1397-1402
  • DOI: 10.1248/cpb.c16-00247
  • NAID: 130005261594
  • ISSN: 0009-2363, 1347-5223
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Identification of Two Sulfated Cholesterol Metabolites Found in the Urine of a Patient with Niemann–Pick Disease Type C as Novel Candidate Diagnostic Markers (2016)
  • Author(s): M.Maekawa, K.Omura, S.Sekiguchi, T.Iida, D.Saigusa, H.Yamaguchi, N.Mano.
  • Journal Title: Mass Spectrometry Volume: 5 Issue: 2 Pages: S0053-S0053
  • DOI: 10.5702/massspectrometry.S0053
  • NAID: 130005285752
  • ISSN: 2186-5116, 2187-137X
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Focused metabolomics using liquid chromatography/electrospray ionization tandem mass spectrometry for analysis of urinary conjugated cholesterol metabolites from patients with Niemann-Pick disease type C and 3β-hydroxysteroid dehydrogenase deficiency (2015)
  • Author(s): Masamitsu Maekawa, Miki Shimada, Kousaku Ohno, Masami Togawa, Hiroshi Nittono, Takashi Iida, Alan F Hofmann, Junichi Goto, Hiroaki Yamaguchi, and Nariyasu Mano
  • Journal Title: Annals of Clinical Biochemistry Volume: 52(5) Issue: 5 Pages: 576-587
  • DOI: 10.1177/0004563214568871
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] 低出生体重児を含む小児におけるUDCAのN-アセチルグルコサミン抱合能について (2016)
  • Author(s): 武井一、入戸野博、飯田隆、村井毅、黒澤隆夫
  • Organizer: 第38回 胆汁酸研究会
  • Place of Presentation: 久留米シティプラザ（福岡県久留米市）
  • Year and Date: 2016-11-26
• [Presentation] 先天性胆汁酸生合成異常症ハイリスク・スクリーニングによるNiemann-Pick 病Ｃ型の早期発見について (2016)
  • Author(s): 成高中之、鈴木光幸、武井一、水落建輝、木村昭彦、塩田光隆、梅津守一郎、十河剛、乾あやの、前川正充、眞野成康、入戸野博、飯田隆、清水俊明
  • Organizer: 第38回 胆汁酸研究会
  • Place of Presentation: 久留米シティプラザ（福岡県久留米市）
  • Year and Date: 2016-11-26