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multi-pathogenesis aging research based on the Down syndrome aneuploidy model

Research Project

Project/Area Number 18KT0026
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeMulti-year Fund
Section特設分野
Research Field Complex Systems Disease Theory
Research InstitutionKumamoto University

Principal Investigator

MINAMI Takashi  熊本大学, 生命資源研究・支援センター, 教授 (00345141)

Co-Investigator(Kenkyū-buntansha) 倉林 伸博  東京大学, 大学院理学系研究科(理学部), 助教 (40581658)
大里 元美  熊本大学, 国際先端医学研究機構, 客員教授 (90314286)
Project Period (FY) 2018-07-18 – 2022-03-31
Project Status Completed (Fiscal Year 2021)
Budget Amount *help
¥18,200,000 (Direct Cost: ¥14,000,000、Indirect Cost: ¥4,200,000)
Fiscal Year 2020: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000)
Fiscal Year 2019: ¥5,850,000 (Direct Cost: ¥4,500,000、Indirect Cost: ¥1,350,000)
Fiscal Year 2018: ¥7,410,000 (Direct Cost: ¥5,700,000、Indirect Cost: ¥1,710,000)
Keywordsダウン症 / 血管内皮細胞 / コレステロール代謝 / 血管新生 / 角膜混濁 / DSCR-1 / NFAT / 動脈硬化 / エピゲノム / ヒストン制御 / bivalent / PTIP / non-canonical PRC1 / 肝細胞 / iPS 細胞 / NAFLD / SREBP2 / 血管病変 / 複合疾病 / ダウン症モデルマウス / 脳神経と血管相互作用 / クロマチン動態 / がん微小環境 / 血管病 / 染色体構造と機能 / 新規モデルマウス構築 / Hi-C 解析 / 脳神経と血管の相互作用 / 行動実験 / ダウン症モデル / クロマチン相互作用 / 異数性 / 造血幹細胞老化
Outline of Final Research Achievements

Down syndrome (DS) is generally recognized as an early aging model. Epidemiologically, DS patients have high risks of cardiac malformation and growth retardation in developmental stages, whereas they significantly reduced incidence of solid tumors, atherosclerosis, and hypertension, as known the aged vascular disease. We have reported DS-related genes timely and spatially separated function under the vascular bed in various organs. Through the research project, we newly discovered that loss of DSCR-1, a critical DS gene, led to hypercholesterolemia, liver steatosis, and corneal opacity, which was exaggerated in the combined null mutation of ApoE. Mechanistically, there is at least a complicated feedforward system with SDF-1/CXCR4, and SREBP2 activation circuits in endothelial cells and hepatocytes, respectively.

Academic Significance and Societal Importance of the Research Achievements

ダウン症は人類遺伝学上最高頻度な先天疾患として知られるが、アンメットメディカルニーズの最たるものでもある。21番染色体トリソミーによってもたらされる複雑なダウン症病態は精神遅滞・早期アルツハイマー病などの神経疾患に留まらず、心奇形・急性白血病・早期歯周病・骨粗鬆症のリスク増加など全身性で多岐にわたる。一方で固形がん罹患率の大幅な低下や動脈硬化が進展しないなど防護的な側面も報告されている。今回我々はダウン症が神経や骨・生殖細胞では早期老化の病態を顕著に示すのに対し、血管においてはダウン症因子 DSCR-1 の安定発現が抗血管新生や抗炎症能を獲得し、加齢に対し防護的に働くことを明らかにした。

Report

(5 results)
  • 2021 Annual Research Report   Final Research Report ( PDF )
  • 2020 Research-status Report
  • 2019 Research-status Report
  • 2018 Research-status Report
  • Research Products

    (52 results)

All 2022 2021 2020 2019 2018 Other

All Int'l Joint Research (5 results) Journal Article (15 results) (of which Int'l Joint Research: 7 results,  Peer Reviewed: 13 results,  Open Access: 14 results) Presentation (21 results) (of which Int'l Joint Research: 7 results,  Invited: 9 results) Remarks (10 results) Funded Workshop (1 results)

  • [Int'l Joint Research] U.Penn/NorthWestern University(米国)

    • Related Report
      2021 Annual Research Report
  • [Int'l Joint Research] U.Penn/NorthWestern University/Harvard Medical School(米国)

    • Related Report
      2020 Research-status Report
  • [Int'l Joint Research] KAIST(韓国)

    • Related Report
      2020 Research-status Report
  • [Int'l Joint Research] Harvard Medical School/U.Penn/MD Anderson Cancer Center(米国)

    • Related Report
      2019 Research-status Report
  • [Int'l Joint Research] MD Anderson Cancer center/Harvard Medical School/U.Penn(米国)

    • Related Report
      2018 Research-status Report
  • [Journal Article] Bivalent-histone-marked immediate-early gene regulation is vital for VEGF-responsive angiogenesis2022

    • Author(s)
      Kanki Yasuharu、Muramatsu Masashi、Miyamura Yuri、Kikuchi Kenta、Higashijima Yoshiki、Nakaki Ryo、Suehiro Jun-ichi、Sasaki Yuji、Kubota Yoshiaki、Koseki Haruhiko、Morioka Hiroshi、Kodama Tatsuhiko、Nakao Mitsuyoshi、Kurotaki Daisuke、Aburatani Hiroyuki、Minami Takashi
    • Journal Title

      Cell Reports

      Volume: 38 Issue: 6 Pages: 110332-110332

    • DOI

      10.1016/j.celrep.2022.110332

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Publisher Correction: The endothelial Dll4?muscular Notch2 axis regulates skeletal muscle mass2022

    • Author(s)
      Fujimaki Shin、Matsumoto Tomohiro、Muramatsu Masashi、Nagahisa Hiroshi、Horii Naoki、Seko Daiki、Masuda Shinya、Wang Xuerui、Asakura Yoko、Takahashi Yukie、Miyamoto Yuta、Usuki Shingo、Yasunaga Kei-ichiro、Kamei Yasutomi、Nishinakamura Ryuichi、Minami Takashi、Fukuda Takaichi、Asakura Atsushi、Ono Yusuke
    • Journal Title

      Nature Metabolism

      Volume: 4 Issue: 3 Pages: 404-404

    • DOI

      10.1038/s42255-022-00560-6

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Loss of Down syndrome critical region-1 leads to cholesterol metabolic dysfunction that exaggerates hypercholesterolemia in ApoE-null background2021

    • Author(s)
      Muramatsu Masashi、Osawa Tsuyoshi、Miyamura Yuri、Nakagawa Suguru、Tanaka Toshiya、Kodama Tatsuhiko、Aburatani Hiroyuki、Sakai Juro、Ryeom Sandra、Minami Takashi
    • Journal Title

      Journal of Biological Chemistry

      Volume: 296 Pages: 100697-100697

    • DOI

      10.1016/j.jbc.2021.100697

    • Related Report
      2021 Annual Research Report 2020 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Lysine Demethylase 5A is Required for MYC Driven Transcription in Multiple Myeloma2021

    • Author(s)
      Ohguchi H、Park Paul M.C.、wang t、Gryder B E.、Ogiya D、kurata k、zhang x、Li D、pei c、Masuda T、Johansson C、Wimalasena V K、Kim Y、Hino S、Usuki S、Kawano Y、Samur M K、Tai Yu-Tzu、Munshi N C.、Matsuoka M、Ohtsuki S、Nakao M、Minami T、Lauberth S、Khan J、Oppermann U、Durbin A D.、Anderson K C.、Hideshima T、Qi J
    • Journal Title

      Blood Cancer Discovery

      Volume: in press Issue: 4 Pages: 370-387

    • DOI

      10.1158/2643-3230.bcd-20-0108

    • Related Report
      2021 Annual Research Report 2020 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] NFAT indicates nucleocytoplasmic damped oscillation via its feedback modulator2021

    • Author(s)
      Muramatsu Masashi、Ito Takeshi、Shimoji Hokuto、Komiya Miko、Miyamura Yuri、Nishiyama Koichi、Suzuki Takashi、Minami Takashi
    • Journal Title

      Biochemical and Biophysical Research Communications

      Volume: 571 Pages: 201-209

    • DOI

      10.1016/j.bbrc.2021.07.072

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] miRNA-1246 in extracellular vesicles secreted from metastatic tumor induces drug resistance in tumor endothelial cells2021

    • Author(s)
      Torii Chisaho、Maishi Nako、Kawamoto Taisuke、Morimoto Masahiro、Akiyama Kosuke、Yoshioka Yusuke、Minami Takashi、Tsumita Takuya、Alam Mohammad Towfik、Ochiya Takahiro、Hida Yasuhiro、Hida Kyoko
    • Journal Title

      Scientific Reports

      Volume: 11 Issue: 1 Pages: 13502-13502

    • DOI

      10.1038/s41598-021-92879-5

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Trib1 promotes the development of acute myeloid leukemia in a Ts1Cje mouse model of Down syndrome2021

    • Author(s)
      Yoshino Seiko、Tanaka Miwa、Sunami Yoshitaka、Takahara Tomoko、Yamazaki Yukari、Homme Mizuki、Niibori-Nambu Akiko、Osato Motomi、Minami Takashi、Ishihara Keiichi、Nakamura Takuro
    • Journal Title

      Leukemia

      Volume: 36 Issue: 2 Pages: 558-561

    • DOI

      10.1038/s41375-021-01384-1

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Calcineurin-nuclear factor for activated T cells (NFAT) signaling in pathophysiology of wound healing2021

    • Author(s)
      Manabe Takahiro、Park Heamin、Minami Takashi
    • Journal Title

      Inflammation and Regeneration

      Volume: 41 Issue: 1 Pages: 26-26

    • DOI

      10.1186/s41232-021-00176-5

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Loss of Down Syndrome Critical Region-1 Mediated-Hypercholesterolemia Accelerates Corneal Opacity Via Pathological Neovessel Formation2020

    • Author(s)
      Muramatsu Masashi、Nakagawa Suguru、Osawa Tsuyoshi、Toyono Tetsuya、Uemura Akiyoshi、Kidoya Hiroyasu、Takakura Nobuyuki、Usui Tomohiko、Ryeom Sandra、Minami Takashi
    • Journal Title

      Arteriosclerosis, Thrombosis, and Vascular Biology

      Volume: 40 Issue: 10 Pages: 2425-2439

    • DOI

      10.1161/atvbaha.120.315003

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] ダウン症因子DSCR-1と病的血管新生2020

    • Author(s)
      南 敬
    • Journal Title

      炎症と免疫

      Volume: 28 Pages: 375-82

    • Related Report
      2020 Research-status Report
    • Open Access
  • [Journal Article] Organ/Tissue-Specific Vascular Endothelial Cell Heterogeneity in Health and Disease2019

    • Author(s)
      Minami Takashi、Muramatsu Masashi、Kume Tsutomu
    • Journal Title

      Biological and Pharmaceutical Bulletin

      Volume: 42 Issue: 10 Pages: 1609-1619

    • DOI

      10.1248/bpb.b19-00531

    • NAID

      130007722463

    • ISSN
      0918-6158, 1347-5215
    • Year and Date
      2019-10-01
    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Loss of Endogenous HMGB2 Promotes Cardiac Dysfunction and Pressure Overload-Induced Heart Failure in Mice2019

    • Author(s)
      Sato M, Miyata K, Tian Z, Kadomatsu T, Ujihara Y, Morinaga J, Horiguchi H, Endo M, Zhao J, Zhu S, Sugizaki T, Igata K, Muramatsu M, Minami T, Ito T, Bianchi ME, Mohri S, Araki K, Node K, Oike Y
    • Journal Title

      Circulation Journal

      Volume: 83 Issue: 2 Pages: 368-378

    • DOI

      10.1253/circj.CJ-18-0925

    • NAID

      130007557092

    • ISSN
      1346-9843, 1347-4820
    • Year and Date
      2019-01-25
    • Related Report
      2019 Research-status Report 2018 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] 血管形成・血管新生を担う転写因子ネットワーク──内皮エピゲノム環境に基づく転写カスケード2019

    • Author(s)
      南 敬
    • Journal Title

      医学のあゆみ 血管新生

      Volume: 270 Pages: 51-56

    • Related Report
      2019 Research-status Report
  • [Journal Article] Downregulation of ERG and FLI1 expression in endothelial cells triggers endothelial-to-mesenchymal transition2018

    • Author(s)
      Nagai Nao、Ohguchi Hiroto、Nakaki Ryo、Matsumura Yoshihiro、Kanki Yasuharu、Sakai Juro、Aburatani Hiroyuki、Minami Takashi
    • Journal Title

      PLOS Genetics

      Volume: 14 Issue: 11 Pages: e1007826-e1007826

    • DOI

      10.1371/journal.pgen.1007826

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Folliculin Regulates Osteoclastogenesis Through Metabolic Regulation2018

    • Author(s)
      3.Baba M, Endoh M, Ma W, Toyama H, Hirayama A, Nishikawa K, Takubo K, Hano H, Hasumi H, Umemoto T, Hashimoto M, Irie N, Esumi C, Kataoka M, Nakagata N, Soga T, Yao M, Kamba T, Minami T, Ishii M, and Suda T.
    • Journal Title

      Journal of Bone and Mineral Research

      Volume: 33 Issue: 10 Pages: 1785-1798

    • DOI

      10.1002/jbmr.3477

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Presentation] エピゲノムダイナミクスを介した 血管新生制御遺伝子群の誘導と炎症・再生制御機構2021

    • Author(s)
      南 敬
    • Organizer
      日本炎症再生医学会
    • Related Report
      2021 Annual Research Report
  • [Presentation] ダウン症関連因子 DSCR-1 による抗加齢・生活習慣病予防効果2021

    • Author(s)
      南 敬
    • Organizer
      抗加齢医学会
    • Related Report
      2021 Annual Research Report
    • Invited
  • [Presentation] ゲノムワイド網羅解析から始まる血管シグナル研究2021

    • Author(s)
      南 敬
    • Organizer
      日本動脈硬化学会
    • Related Report
      2021 Annual Research Report
    • Invited
  • [Presentation] The Down syndrome-related gene sets regulate vascular inflammation via a cytokine storm2021

    • Author(s)
      Takashi Minami
    • Organizer
      44 th 日本分子生物学会
    • Related Report
      2021 Annual Research Report
    • Invited
  • [Presentation] 温故知新;古くて新しいGATA 転写因子研究の最前線2021

    • Author(s)
      南 敬
    • Organizer
      日本生化学会
    • Related Report
      2021 Annual Research Report
  • [Presentation] ヒストンメチル化ダイナミクスを介した内皮分化 及び血管新生応答制御機構の解明2020

    • Author(s)
      南 敬
    • Organizer
      第93回日本生化学会
    • Related Report
      2020 Research-status Report
  • [Presentation] VEGF-mediated unique epigenetic modifications initiated accurate angiogenesis via bivalent marked gene-set activation in endothelium2020

    • Author(s)
      Takashi Minami
    • Organizer
      IVBM2020
    • Related Report
      2020 Research-status Report
    • Int'l Joint Research / Invited
  • [Presentation] Developmental Endothelium Specific Molecule (DESM) regulates angiogenesis and tumor progression2020

    • Author(s)
      Yuri Miyamura, Masashi Muramatsu, and Takashi Minami
    • Organizer
      IVBM2020
    • Related Report
      2020 Research-status Report
    • Int'l Joint Research
  • [Presentation] Endothelial cell stabilize and anti-cancer strategy based on the HSA21 trisomy genes; ERG and DSCR-1 function.2020

    • Author(s)
      Takashi Minami
    • Organizer
      第43回日本分子生物学会
    • Related Report
      2020 Research-status Report
  • [Presentation] Bivalent Histone-marked Genes Transcription is Vital for Postnatal Angiogenesis2020

    • Author(s)
      Takashi Minami
    • Organizer
      第85回日本循環器学会
    • Related Report
      2020 Research-status Report
    • Int'l Joint Research
  • [Presentation] Uncovering VEGF-stimulated variable epigenome landscape in endothelium2019

    • Author(s)
      Minami, T
    • Organizer
      Gordon Research Conference 2019 Epigenetic Regulation of Cardiovascular Disease
    • Related Report
      2019 Research-status Report
    • Int'l Joint Research
  • [Presentation] Homeostasis in NFAT1-Down syndrome critical region-1 signaling is critical for regulation of proper vessel formation and vascular integrity2019

    • Author(s)
      Muramatsu M., Ryeom S., Uemura A., and Minami T.
    • Organizer
      第3回Asia Australia Vascular Biology Meeting(AAVBM)
    • Related Report
      2019 Research-status Report
    • Int'l Joint Research / Invited
  • [Presentation] Homeostasis in NFAT-DSCR-1 signaling is critical for initial epigenetic conversion and the following proper vessel formation2019

    • Author(s)
      Minami, T
    • Organizer
      NIH Vascular Annual Seminar series
    • Related Report
      2019 Research-status Report
    • Int'l Joint Research / Invited
  • [Presentation] VEGF 刺激によるヒストンダイナミクスを介した内皮分化 及び血管分岐応答制御機構の解明2019

    • Author(s)
      南 敬
    • Organizer
      CVMW2019
    • Related Report
      2019 Research-status Report
    • Invited
  • [Presentation] ダウン症因子DSCR-1 の血管分岐への機構解析2019

    • Author(s)
      村松 昌、南 敬
    • Organizer
      第42回日本分子生物学会年会
    • Related Report
      2019 Research-status Report
  • [Presentation] A novel endothelial cell specific-gene, DESM, regulated pathological angiogenesis2019

    • Author(s)
      Yuri Miyamura, Masashi Muramatsu, Takashi Minami
    • Organizer
      第78回日本癌学会学術総会
    • Related Report
      2019 Research-status Report
  • [Presentation] 血管内皮でのShear stressによるNuclear Factor Activated T-cells (NFAT)の活性化動態2019

    • Author(s)
      下地 北斗、赤星 彰也、村松 昌、西山 功一、南 敬
    • Organizer
      第43回 蛋白質と酵素の構造と機能に関する九州シンポジウム
    • Related Report
      2019 Research-status Report
  • [Presentation] ヒト21トリソミー関連遺伝子 (ERG, DSCR-1) による内皮恒常性維持と抗がん作用2018

    • Author(s)
      南 敬
    • Organizer
      日本分子生物学会
    • Related Report
      2018 Research-status Report
    • Invited
  • [Presentation] ダウン症モデルマウスを用いた血管恒常性制御機構解析2018

    • Author(s)
      村松 昌、南 敬
    • Organizer
      日本分子生物学会
    • Related Report
      2018 Research-status Report
    • Invited
  • [Presentation] ダウン症因子 DSCR-1 の欠損は脂質代謝異常から加齢に伴う病的血管新生を誘発する2018

    • Author(s)
      村松 昌、南 敬
    • Organizer
      心血管代謝週間 CVMW2018
    • Related Report
      2018 Research-status Report
  • [Presentation] Dynamically and Epigenetically Coordinated Erg and Fli1 Transcription Factor Expression is Indispensable for Endothelial Cell Differentiation and Maintenance2018

    • Author(s)
      Takashi Minami
    • Organizer
      AHA scientific session 2018
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research
  • [Remarks] ダウン症関連因子が脂肪肝を防ぐ仕組みについてー論文を JBC に報告しました

    • URL

      http://irda-vascular.kuma-u.jp/news/2021/06/-jbc-httpsdoiorg101016jjbc2021100697.html

    • Related Report
      2021 Annual Research Report
  • [Remarks] 新学術領域研究―数理の宿題を1つ完成しました

    • URL

      http://irda-vascular.kuma-u.jp/news/2021/08/1-1.html

    • Related Report
      2021 Annual Research Report
  • [Remarks] がんや慢性炎症などの病的血管新生を引き起こす ユニークかつダイナミックなエピゲノム修飾

    • URL

      https://www.kumamoto-u.ac.jp/whatsnew/seimei-sentankenkyu/20220208

    • Related Report
      2021 Annual Research Report
  • [Remarks] ダウン症関連遺伝子が加齢による角膜混濁を防護、熊本大学が発見

    • URL

      https://univ-journal.jp/54740/

    • Related Report
      2020 Research-status Report
  • [Remarks] 2020.2.4-5 文科省先端モデル動物支援成果発表会に参加しました

    • URL

      http://irda-vascular.kuma-u.jp/news/2020/02/202024-5.html

    • Related Report
      2019 Research-status Report
  • [Remarks] 下地君が若手優秀発表賞に選ばれました

    • URL

      http://irda-vascular.kuma-u.jp/news/2019/09/post-36.html

    • Related Report
      2019 Research-status Report
  • [Remarks] 当研究室卒業生の論文がPLOS Genetics に受理されました

    • URL

      http://irda-vascular.kuma-u.jp/news/2018/12/plos-genetics.html

    • Related Report
      2019 Research-status Report 2018 Research-status Report
  • [Remarks] 第26回日本血管生物医学会にて、村松助教が Best of YIA に選ばれました

    • URL

      http://irda-vascular.kuma-u.jp/news/2018/12/-best-of-yia.html

    • Related Report
      2018 Research-status Report
  • [Remarks] 第2回九州血管生物医学会 (KVBM) 開催しました

    • URL

      http://irda-vascular.kuma-u.jp/news/2018/11/-kvbm.html

    • Related Report
      2018 Research-status Report
  • [Remarks] 分子血管制御分野の研究成果がPlos Geneticsに掲載されました

    • URL

      http://www.pharm.kumamoto-u.ac.jp/news_topics/2018/11/plos-genetics.html

    • Related Report
      2018 Research-status Report
  • [Funded Workshop] The 2nd KU-KAIST Joint symposium2019

    • Related Report
      2018 Research-status Report

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Published: 2018-07-20   Modified: 2023-01-30  

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