Study on the pathogenesis of upper airway obstruction through neuronal receptor impairment in pediatric obstructive sleep apnea

• Project/Area Number: 16K11778
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Orthodontics/Pediatric dentistry
• Research Institution: Tokyo Medical and Dental University
• Principal Investigator: Hosomichi Jun 東京医科歯科大学, 大学院医歯学総合研究科, 講師 (00420258)
• Co-Investigator(Kenkyū-buntansha): 小野 卓史 東京医科歯科大学, 大学院医歯学総合研究科, 教授 (30221857) ; 吉田 謙一 東京医科大学, 医学部, 主任教授 (40166947) ; 前田 秀将 東京医科大学, 医学部, 講師 (60407963)
• Research Collaborator: OISHI Shuji ; KUMA Yoichiro ; SATO Moe ; HATANO Kasumi ; HONG Haixin ; LEKVIJITTADA Kochakorn ; KIMURA Ryo ; WONGKITIKAMJORN Wirongrong
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2018: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2017: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2016: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 閉塞性睡眠時無呼吸症候群 / 間欠的低酸素曝露 / 成長期 / ラットモデル / 交感神経受容体 / 小児 / 顎骨成長 / 上部気道閉塞 / 間欠的低酸素暴露 / 動物モデル / 成長期ラットモデル / 閉塞性無呼吸症候群 / 成長期動物 / 歯学 / 睡眠呼吸障害

Outline of Final Research Achievements

Impaired craniofacial growth, upper airway inflammation and abnormal upper airway neuromotor tone have been implicated in the development of obstructive sleep apnea (OSA) in children. Intermittent hypoxia (IH) is a main characteristic of pediatric OSA. However, there are no studies to clarify the mechanism of craniofacial pathology caused by IH in the growth periods, including bone and cartilage metabolic changes, upper airway inflammation and impaired muscle functions. In this study using growing animal model to exposed to IH, we firstly showed the growth stage-dependent craniofacial pathogenesis in animal models to exposed to IH. Finally, we suggest the role of beta2 adrenergic receptors in craniofacial pathology caused by IH during growth.

Academic Significance and Societal Importance of the Research Achievements

これまで小児OSA患者を対象とした成長障害、上部気道炎症および気道拡張筋の機能変調に関する臨床調査および小児OSAの病態を再現した実験モデル動物を用いた研究は、国内外を問わず少なく、本疾患における気道狭窄の増悪に貢献する、上記の顎顔面領域の病態形跡機構の詳細は、未だに解明されていない。本研究は、小児OSA患者の睡眠呼吸障害を再現した動物モデルを用いて、①睡眠呼吸障害における顎顔面領域の病態形成が発達段階の違いに依存すること、②睡眠呼吸障害における顎顔面領域の病態形成への交感神経β2受容体の機能亢進の関与を、初めて明らかにするとともに、小児歯科医療の睡眠呼吸障害への関与の重要性を示す基盤となる。

Research Products

• [Int'l Joint Research] チュラロンコーン大学歯学部(タイ)
• [Int'l Joint Research] Chulalongkorn University(タイ)
• [Journal Article] Localization of leucine-rich repeat-containing G-protein-coupled receptor 5- and Ki67-positive periodontal cells expressing runt-related transcription factor 2 during tooth movement (2018)
  • Author(s): Hosomichi J, Shibutani N, Yamaguchi H, Hatano K, Kuma Y, Suzuki T, Kaneko S, Ono T.
  • Journal Title: Orthod Waves. Volume: 77 Issue: 4 Pages: 197-208
  • DOI: 10.1016/j.odw.2018.07.002
  • Peer Reviewed
• [Journal Article] Optogenetic manipulation of intracellular calcium by BACCS promotes differentiation of MC3T3-E1 cells (2018)
  • Author(s): Sato Moe、Asano Toshifumi、Hosomichi Jun、Ono Takashi、Nakata Takao
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 506 Issue: 3 Pages: 716-722
  • DOI: 10.1016/j.bbrc.2018.10.107
  • Peer Reviewed
• [Journal Article] Intermittent hypoxia causes mandibular growth retardation and macroglossia in growing rats. (2016)
  • Author(s): Hosomichi J, Kuma YI, Oishi S, Nagai H, Maeda H, Usumi-Fujita R, Shimizu Y, Kaneko S, Shitano C, Suzuki JI, Yoshida KI, Ono T.
  • Journal Title: Am J Orthod Dentofacial Orthop. Volume: 151 Issue: 2 Pages: 363-371
  • DOI: 10.1016/j.ajodo.2016.02.033
  • Peer Reviewed
• [Journal Article] Intermittent Hypoxia Influences Alveolar Bone Proper Microstructure via Hypoxia-Inducible Factor and VEGF Expression in Periodontal Ligaments of Growing Rats. (2016)
  • Author(s): Oishi S, Shimizu Y, Hosomichi J, Kuma Y, Maeda H, Nagai H, Usumi-Fujita R, Kaneko S, Shibutani N, Suzuki JI, Yoshida KI, Ono T.
  • Journal Title: Front Physiol. Volume: 7 Pages: 416-416
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] 光遺伝学ツールBACCSを用いた骨芽細胞分化メカニズムの制御. (2019)
  • Author(s): 佐藤 萌, 浅野 豪文, 細道 純, 小野 卓史, 中田 隆夫.
  • Organizer: 第124回日本解剖学会総会・全国学術集会
• [Presentation] 光遺伝学ツールBACCSを用いた骨芽細胞分化メカニズムの制御. (2019)
  • Author(s): 佐藤 萌, 浅野 豪文, 細道 純, 小野 卓史, 中田 隆夫.
  • Organizer: 第11回 CBIR 若手インスパイアシンポジウム
• [Presentation] Effect of prenatal intermittent hypoxia on muscle development in offspring. (2019)
  • Author(s): Wongkitikamjorn W, Hosomichi J, Wada E, Maeda H, Satrawaha S, Hong H, Hayashi Y, Yoshida K, Ono T.
  • Organizer: 97th General Session and Exhibition of the International Association for Dental Research (IADR)
  • Int'l Joint Research
• [Presentation] Optogenetic manipulation of intracellular calcium by blue light-activated Ca2+ channel switch promotes osteogenic differentiation of MC3T3-E1 cells. (2019)
  • Author(s): Sato M, Asano T, Hosomichi J, Ono T, Nakata T.
  • Organizer: 95th congress of the European Orthodontic Society
  • Int'l Joint Research
• [Presentation] Different effects of intermittent hypoxia on mandibular growth in the juvenile and adolescent rats. (2018)
  • Author(s): Hong H, Hosomichi J, Maeda M, Lekvijittada K, Oishi S, Kuma Y, Yamaguchi H, Ishida Y, Usumi-Fujita R, Shimizu Y, Kaneko S, Suzuki JI, Yoshida KI, Ono T.
  • Organizer: Wuhan University PhD seminar
  • Int'l Joint Research
• [Presentation] β2-adrenergic antagonist butoxamine reduces the mandibular growth retardation caused by intermittent hypoxia in adolescent rats. (2018)
  • Author(s): Hong H, Hosomichi J, Maeda H, Lekvijittada K, Oishi S, Kuma Y, Yamaguchi H, Ishida Y, Usumi-Fujita R, Shimizu Y, Kaneko S, Suzuki J, Yoshida K, Ono T.
  • Organizer: 第77回日本矯正歯科学会大会
• [Presentation] 光遺伝学を用いた骨芽細胞分化メカニズムの解明と制御. (2018)
  • Author(s): 佐藤 萌, 浅野 豪文, 細道 純, 石田 雄之, 臼見 莉沙, 清水 康広, 金香 佐和, 中田 隆夫, 小野 卓史.
  • Organizer: 第77回日本矯正歯科学会大会
• [Presentation] β2-adrenergic antagonist butoxamine reduces the mandibular growth retardation caused by intermittent hypoxia in adolescent rats. (2018)
  • Author(s): Hong H, Hosomichi J, Maeda H, Lekvijittada K, Oishi S, Kuma Y, Yamaguchi H, Ishida Y, Usumi-Fujita R, Shimizu Y, Kaneko S, Suzuki J, Yoshida K, Ono T.
  • Organizer: 国際歯科研究学会日本部会（JADR）Hatton Award 2019 国内最終選考会
• [Presentation] Differential effects of intermittent hypoxia on phenotypic and metabolic features of airway muscles in weaning- and adolescent-aged rats. (2018)
  • Author(s): Hosomichi J, Maeda H, Yoichiro Kuma, Oishi S, Yoshida KI, Ono T.
  • Organizer: 第5回東京医科大学記念会館ポスター発表懇談会.
• [Presentation] Influences of intermittent hypoxia on condylar growth: A study in infant rats. (2018)
  • Author(s): Lekvijittada K, Hosomichi J, Maeda H, Hong H, Changsiripun C, Kuma Y, Oishi S, Yamaguchi H, Ishida Y, Usumi-Fujita R, Shimizu Y, Kaneko S, Suzuki JI, Yoshida KI, Ono T.
  • Organizer: 第5回東京医科大学記念会館ポスター発表懇談会.
• [Presentation] Influences of intermittent hypoxia on condylar growth: A study in infant rats. (2018)
  • Author(s): Lekvijittada K, Hosomichi J, Maeda H, Hong H, Changsiripun C, Kuma Y, Oishi S, Yamaguchi H, Ishida Y, Usumi-Fujita R, Shimizu Y, Kaneko S, Suzuki JI, Yoshida KI, Ono T.
  • Organizer: The 11th Asian Pacific Orthodontic Conference.
  • Int'l Joint Research
• [Presentation] Differential effects of intermittent hypoxia on phenotypic and metabolic features of airway muscles in weaning- and adolescent-aged rats. (2017)
  • Author(s): Hosomichi J, Maeda H, Yoichiro Kuma, Oishi S, Yoshida KI, Ono T.
  • Organizer: World Sleep 2017.
  • Int'l Joint Research
• [Presentation] 矯正的歯の移動時におけるKi67およびLGR5陽性歯根膜細胞の局在変化. (2017)
  • Author(s): 細道純, 鈴木拓海, 渋谷直樹, 畑野香澄, 山口博之, 隈陽一郎, 金香佐和, 笠原由紀, 大石修史, 臼見莉沙, 清水康広, 小野卓史.
  • Organizer: 第76 回日本矯正歯科学会大会.
• [Presentation] 成長期における間欠的低酸素曝露がラット鼻腔気道の炎症亢進と形態変化をもたらす. (2016)
  • Author(s): 隈陽一郎, 臼見莉沙, 細道純, 大石修史, 山口博之, 沖藤明日香, 清水康広, 渋谷直樹, 石田雄之, 金香佐和, 鈴木淳一, 吉田謙一, 小野卓史.
  • Organizer: 第75 回日本矯正歯科学会大会
  • Place of Presentation: アスティとくしま(徳島県・徳島市）