Novel therapeutic approach from Marfan syndrome for the drug discovery of periodontal diseases

• Project/Area Number: 17K17588
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Conservative dentistry; Periodontology
• Research Institution: Kyushu Dental College (2021); Iwate University (2019-2020); Tohoku University (2017-2018)
• Principal Investigator: Orimoto Ai 九州歯科大学, 歯学部, 助教 (30710967)
• Project Period (FY): 2017-04-01 – 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 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2017: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
• Keywords: ADAMTSL6β / 結合組織疾患 / 微細線維 / fibrillin-1 / 微細線維形成 / マルファン症候群 / ADAMTS superfamily / ADAMTS4

Outline of Final Research Achievements

Fibrillin‐1 is the major component of extracellular matrix microfibrils. Although ADAMTSL (a disintegrin and metalloproteinase with thrombospondin motifs‐like) 6β is one of the fibrillin‐1 binding proteins, the detailed mechanism underlying the involvement of ADAMTSL6β in microfibril formation remains unclear. In this study, we created deletion mutants of ADAMTSL6β and examined their interactions with fibrillin‐1 assembly.
Our data showed that the third thrombospondin type I domain of ADAMTSL6β influence the microfibril formation.

Academic Significance and Societal Importance of the Research Achievements

マルファン症候群（MFS）は、FBN-1のミスセンス変異を原因とする遺伝性結合組織疾患である。ADAMTSL6βは、FBN-1と結合し、微細線維の形成を促進することが報告されていたが、マルチドメイン構造を持つADAMTSL6βのどの領域が、FBN-1と結合するかは不明であった。本研究では、ADAMTSL6βのFBN-1に対する結合ドメイン解析により、ADAMTSL6βの3番目のTSP ドメインを介して微細線維の形成を促進することを証明した。本研究成果は、マルファン症候群を含む他の結合組織疾患に対する病態解明および有効な治療技術へと発展する可能性が考えられる。

Research Products

• [Journal Article] Transcriptome analysis to identify the downstream genes of androgen receptor in dermal papilla cells. (2021)
  • Author(s): Furuya K, Fujibayashi S, Wu T, Takahashi K, Takase S, Orimoto A, Sugano E, Tomita H, Kashiwagi S, Kiyono T, Ishii T, Fukuda T.
  • Journal Title: BMC Genom Data. Volume: 23(1) Issue: 1 Pages: 1-10
  • DOI: 10.1186/s12863-021-01018-6
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The transcriptome of wild-type and immortalized corneal epithelial cells. (2021)
  • Author(s): Furuya K, Wu T, Orimoto A, Sugano E, Tomita H, Kiyono T, Kurose T, Takai Y, Fukuda T.
  • Journal Title: Sci Data. Volume: 8(1) Issue: 1 Pages: 126-126
  • DOI: 10.1038/s41597-021-00908-9
  • NAID: 120007175170
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Establishment of human airway epithelial cells with doxycycline-inducible cell growth and fluorescence reporters (2021)
  • Author(s): Orimoto Ai、Takahashi Kohei、Imai Masaki、Kiyono Tohru、Kawaoka Yoshihiro、Fukuda Tomokazu
  • Journal Title: Cytotechnology Volume: 73 Issue: 4 Pages: 555-569
  • DOI: 10.1007/s10616-021-00477-0
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Combinatorial expression of cell cycle regulators is more suitable for immortalization than oncogenic methods in dermal papilla cells (2021)
  • Author(s): Fukuda Tomokazu、Furuya Kai、Takahashi Kouhei、Orimoto Ai、Sugano Eriko、Tomita Hiroshi、Kashiwagi Sayo、Kiyono Tohru、Ishii Tsuyoshi
  • Journal Title: iScience Volume: 24 Issue: 1 Pages: 101929-101929
  • DOI: 10.1016/j.isci.2020.101929
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Efficient immortalization of human dental pulp stem cells with expression of cell cycle regulators with the intact chromosomal condition (2020)
  • Author(s): Orimoto Ai、Kyakumoto Seiko、Eitsuka Takahiro、Nakagawa Kiyotaka、Kiyono Tohru、Fukuda Tomokazu
  • Journal Title: PLOS ONE Volume: 15 Issue: 3 Pages: e0229996-e0229996
  • DOI: 10.1371/journal.pone.0229996
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] ADAMTSL6β promotes fibrillin‐1 microfibril assembly, which is possibly mediated via binding through the third thrombospondin type I domain to fibrillin‐1 (2020)
  • Author(s): Orimoto Ai、Fukuda Tomokazu
  • Journal Title: Cell Biology International Volume: 00 Issue: 7 Pages: 1-11
  • DOI: 10.1002/cbin.11337
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Human Derived Immortalized Dermal Papilla Cells With a Constant Expression of Testosterone Receptor (2020)
  • Author(s): Fukuda Tomokazu、Takahashi Kouhei、Takase Shin、Orimoto Ai、Eitsuka Takahiro、Nakagawa Kiyotaka、Kiyono Tohru
  • Journal Title: Frontiers in Cell and Developmental Biology Volume: 8 Pages: 157-173
  • DOI: 10.3389/fcell.2020.00157
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Primary and immortalized cell lines derived from the Amami rabbit (Pentalagus furnessi) and evolutionally conserved cell cycle control with CDK4 and Cyclin D1. (2020)
  • Author(s): Orimoto A, Katayama M, Tani T, Ito K, Eitsuka T, Nakagawa K, Inoue-Murayama M, Onuma M, Kiyono T, Fukuda T
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 525 Issue: 4 Pages: 1046-1053
  • DOI: 10.1016/j.bbrc.2020.03.036
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Metal ions from S‐PRG filler have the potential to prevent periodontal disease (2017)
  • Author(s): Yoko Iwamatsu‐Kobayashi, Syouta Abe, Yoshiyasu Fujieda, Ai Orimoto, Masafumi Kanehira, Keisuke Handa, Venkata Suresh Venkataiah, Wei Zou, Masaki Ishikawa, Masahiro Saito
  • Journal Title: Clinical and Experiment Dental Research Volume: 3 Issue: 4 Pages: 126-133
  • DOI: 10.1002/cre2.70
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] 変異型CDK4,サイクリンD1,TERTの３遺伝子導入による効率の良い無限分裂ヒト歯髄幹細胞の樹立 (2020)
  • Author(s): 折本 愛、客本斉子、永塚貴弘、仲川清隆、 清野 透、福田智一
  • Organizer: 第52回 日本結合組織学会学術大会
• [Presentation] ADAMTSL6βを介したMarfan症候群の解離性大動脈瘤発症機構の解析 (2017)
  • Author(s): 折本 愛, 二木 正晴, 石河 真幸, 半田 慶介, 齋藤 正寛
  • Organizer: 第146回日本歯科保存学会春期学術大会
• [Presentation] ADAMTS superfamilyによるMarfan症候群の解離性大動脈瘤発症機構の解析 (2017)
  • Author(s): 折本愛、石河 真幸、半田慶介、千々岩みゆき、望月早月、村澤祐介、磯貝善蔵、岡田保典、齋藤正寛
  • Organizer: 第49回日本結合組織学会
• [Presentation] ADAMTSL6β exacerbates tissue destruction of aortic aneurysm and dissection in Marfan syndrome mouse model through promotion of ADAMTS4 activity (2017)
  • Author(s): Ai Orimoto, Yousuke Murasawa, Zenzo Isogai, Satsuki Mochizuki, Hiroyuki Kumamoto, Satoshi Fukumoto, Yasunori Okada and Masahiro Saito
  • Organizer: Elastin, Elastic Fibers & Microfibrils Gordon Research Conference
  • Int'l Joint Research