Development of a new treatment for obese diabetic periodontitis using anti-inflammatory miRNA-encapsulating exosomes

• Project/Area Number: 18K17071
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 57030:Conservative dentistry-related
• Research Institution: Kyushu University
• Principal Investigator: SANO TOMOMI 九州大学, 歯学研究院, 助教 (50782075)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2019: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000); Fiscal Year 2018: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: 炎症 / 肥満 / 歯周病 / microRNA / 歯周炎 / 慢性炎症 / マクロファージ / 脂肪組織 / 歯周組織 / エクソソーム / インスリン抵抗性

Outline of Final Research Achievements

In vitro study revealed that miR-146a transfection into either adipocytes or gingival fibroblasts, has resulted in a reduced cytokine gene expression, observed on co-culturing the cells with macrophages in the presence of LPS, in comparison to the control miRNA transfected. Similarly, miR-146a transfection into macrophages resulted in a reduced expression of TNF-α gene and protein in response to LPS stimulation.
In vivo study revealed that a continuous intravenous miR-146a administration into mice via tail vein, protected the mice from developing obesity and the inflammatory cytokine gene expression was down-regulated in both adipose and periodontal tissues.

Academic Significance and Societal Importance of the Research Achievements

TNF-α中和抗体添加によりサイトカイン産生が抑制するという過去の結果から、今回用いた共培養系においてもmiR-146a-5pがマクロファージからのTNF-α発現を抑制し、結果的に炎症抑制につながったと考える。
miR-146a-5pは肥満糖尿病などにおいて脂肪・歯周組織の炎症に共通の制御因子として働く可能性がある。

Research Products

• [Journal Article] Adipocyte-specific GPRC6A ablation promotes diet-induced obesity by inhibiting lipolysis (2021)
  • Author(s): Mukai Satoru、Mizokami Akiko、Otani Takahito、Sano Tomomi、Matsuda Miho、Chishaki Sakura、Gao Jing、Kawakubo-Yasukochi Tomoyo、Tang Ronghao、Kanematsu Takashi、Takeuchi Hiroshi、Jimi Eijiro、Hirata Masato
  • Journal Title: Journal of Biological Chemistry Volume: 296 Pages: 100274-100274
  • DOI: 10.1016/j.jbc.2021.100274
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Expression of PRIP, a phosphatidylinositol 4,5-bisphosphate binding protein, attenuates PI3K/AKT signaling and suppresses tumor growth in a xenograft mouse model (2021)
  • Author(s): Maetani Yuka、Asano Satoshi、Mizokami Akiko、Yamawaki Yosuke、Sano Tomomi、Hirata Masato、Irifune Masahiro、Kanematsu Takashi
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 552 Pages: 106-113
  • DOI: 10.1016/j.bbrc.2021.03.045
  • Peer Reviewed / Open Access
• [Journal Article] Anti-inflammatory Effects of miRNA-146a Induced in Adipose and Periodontal Tissues (2020)
  • Author(s): Taiki Sanada, Tomomi Sano, Yusuke Sotomaru, Rehab Alshargabi, Yosuke Yamawaki, Akiko Yamashita, Hiroaki Matsunaga, Misaki Iwashita, Takanori Shinjo, Takashi Kanematsu, Tomoichiro Asano, Fusanori Nishimura
  • Journal Title: Biochem Biophys Rep. Volume: Jul Pages: 100757-100757
  • DOI: 10.1016/j.bbrep.2020.100757
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] SPOCK1 is a novel inducer of epithelial to mesenchymal transition in drug-induced gingival overgrowth (2020)
  • Author(s): Alshargabi Rehab、Sano Tomomi、Yamashita Akiko、Takano Aiko、Sanada Taiki、Iwashita Misaki、Shinjo Takanori、Fukuda Takao、Sanui Terukazu、Kishida Shosei、Nishimura Fusanori
  • Journal Title: Scientific Reports Volume: 10 Issue: 1 Pages: 9785-9785
  • DOI: 10.1038/s41598-020-66660-z
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] SPOCK1 induces adipose tissue maturation: New insights into the function of SPOCK1 in metabolism (2020)
  • Author(s): Alshargabi Rehab、Shinjo Takanori、Iwashita Misaki、Yamashita Akiko、Sano Tomomi、Nishimura Yuki、Hayashi Masato、Zeze Tatsuro、Fukuda Takao、Sanui Terukazu、Nishimura Fusanori
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 533 Issue: 4 Pages: 1076-1082
  • DOI: 10.1016/j.bbrc.2020.09.129
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Ccr7 null mice are protected against diet-induced obesity via Ucp1 upregulation and enhanced energy expenditure (2019)
  • Author(s): Sano Tomomi、Sanada Taiki、Sotomaru Yusuke、Shinjo Takanori、Iwashita Misaki、Yamashita Akiko、Fukuda Takao、Sanui Terukazu、Asano Tomoichiro、Kanematsu Takashi、Nishimura Fusanori
  • Journal Title: Nutrition & Metabolism Volume: 16 Issue: 1 Pages: 43-43
  • DOI: 10.1186/s12986-019-0372-5
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Possible involvement of normalized Pin1 expression level and AMPK activation in the molecular mechanisms underlying renal protective effects of SGLT2 inhibitors in mice (2019)
  • Author(s): Inoue Masa-Ki、Matsunaga Yasuka、Nakatsu Yusuke、Yamamotoya Takeshi、Ueda Koji、Kushiyama Akifumi、Sakoda Hideyuki、Fujishiro Midori、Ono Hiraku、Iwashita Misaki、Sano Tomomi、Nishimura Fusanori、Morii Kenichi、Sasaki Kensuke、Masaki Takao、Asano Tomoichiro
  • Journal Title: Diabetology & Metabolic Syndrome Volume: 11 Issue: 1 Pages: 57-57
  • DOI: 10.1186/s13098-019-0454-6
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Dental pulp cell-derived powerful inducer of TNF-α comprises PKR containing stress granule rich microvesicles. (2019)
  • Author(s): Suzuki S, Fukuda T, Nagayasu S, Nakanishi J, Yoshida K, Hirata-Tsuchiya S, Nakao Y, Sano T, Yamashita A, Yamada S, Ohta K, Shiba H, Nishimura F.
  • Journal Title: Scientific Reports Volume: 9 Issue: 1 Pages: 3825-3825
  • DOI: 10.1038/s41598-019-40046-2
  • Peer Reviewed / Open Access
• [Journal Article] Prolyl Isomerase Pin1 Suppresses Thermogenic Programs in Adipocytes by Promoting Degradation of Transcriptional Co-activator PRDM16. (2019)
  • Author(s): Nakatsu Y, Matsunaga Y, Yamamotoya T, Ueda K, Inoue MK, Mizuno Y, Nakanishi M, Sano T, Yamawaki Y, Kushiyama A, Sakoda H, Fujishiro M, Ryo A, Ono H, Minamino T, Takahashi SI, Ohno H, Yoneda M, Takahashi K, Ishihara H, Katagiri H, Nishimura F, Kanematsu T, Yamada T, Asano T.
  • Journal Title: Cell Rep. Volume: 26 Issue: 12 Pages: 3221-3230
  • DOI: 10.1016/j.celrep.2019.02.066
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] 脂肪・歯周組織で発現誘導されるmiRNAによる抗炎症効果の検討 (2019)
  • Author(s): 眞田大樹、佐野朋美、岩下未咲、山下明子、兼松隆、西村英紀
  • Organizer: 第62回春季日本歯周病学会学術大会
• [Presentation] 脂肪・歯周組織で発現誘導されるmiRNA-146aによる抗炎症効果の検討 (2019)
  • Author(s): 真田大樹、佐野朋美、松永絋明、Rehab Alshargabi、岩下未咲、山下明子、西村英紀
  • Organizer: 第151回日本歯科保存学会2019年度秋季学術大会
• [Presentation] IDENTIFICATION OF MICRORNAS INVOLVED IN ADIPOSE TISSUE INFLAMMATION. (2019)
  • Author(s): Sano T, Sanada T, Rehab A, Sotomaru Y, Iwashita M, Yamashita A, Nishimura F.
  • Organizer: 13th Asian Pacific Society of Periodontology Meeting
  • Int'l Joint Research
• [Presentation] Anti-inflammatory effects of miRNA-146a induced in adipose and periodontal tissues. (2019)
  • Author(s): Tomomi Sano, Taiki Sanada, Rehab Alshargabi, Akiko Yamashita, Hiroaki Matsunaga, Misaki Iwashita, Fusanori Nishimura.
  • Organizer: The 59th General Session of Korean Academy of Periodontology
  • Int'l Joint Research
• [Presentation] Identification of microRNAs involved in adipose tissue inflammation. (2019)
  • Author(s): Sano T, Sanada T, Rehab A, Shinjo T, Li R, Iwashita M, Yamashita A, Nishimura F.
  • Organizer: 2019 Taiwan Academy of Periodontology Annual Meeting and International Symposium
  • Int'l Joint Research
• [Presentation] 炎症脂肪/歯周組織における抗炎症分子の探索研究 (2018)
  • Author(s): 眞田大樹、佐野朋美、福田隆男、岩下未咲、山下明子、藤田剛、讃井彰一、栗原英見、西村英紀
  • Organizer: 第148回日本歯科保存学会2018年度春季学術大会
• [Presentation] CCR7欠損マウスにおける脂肪および歯周組織炎症抑制機序の考察 (2018)
  • Author(s): 佐野朋美、眞田大樹、竹村翼、Rehab Alshargabi、岩下未咲、山下明子、藤田剛、栗原英見、西村英紀
  • Organizer: 第61回秋季日本歯周病学会学術大会
• [Presentation] The Role of Proteoglycans In Drug Induced Gingival Overgrowth (DIGO) (2018)
  • Author(s): Rehab Alshargabi, Tomomi Sano, Akiko Yamashita, Taiki Sanada, Takao Fukuda, Misaki Iwashita, Terukazu Sanui, Fusanori Nishimura
  • Organizer: 第149回日本歯科保存学会2018年度秋季学術大会
• [Presentation] 脂肪・歯周組織における抗炎症効果の検討 (2018)
  • Author(s): 眞田大樹、佐野朋美、西村英紀
  • Organizer: 平成30年度 日本歯周病学会九州五大学・日本臨床歯周病学会九州支部・合同研修会
• [Presentation] Increased energy expenditure and resistance to obesity in CCR7KO mice. (2018)
  • Author(s): Sano T, Sanada T, Shinjo T, Iwashita M, Yamashita A, Kanematsu T, Nishimura F.
  • Organizer: The 96th General Session of the IADR
  • Int'l Joint Research
• [Book] 徹底解説！糖尿病合併症管理・フォローアップ (2021)
  • Author(s): 佐野朋美他
  • Total Pages: 204
  • Publisher: 文光堂
  • ISBN: 9784830613975
• [Book] 月刊糖尿病 6「歯周病と糖尿病」． Vol.11 No.4 (56-61) (2019)
  • Author(s): 佐野朋美、西村英紀
  • Total Pages: 112
  • Publisher: 医学出版
  • ISBN: 9784287821152