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大学・研究所にある論文を検索できる 「高濃度酸素性肺障害および新生児慢性肺疾患における肺内代謝および修復に関する研究」の論文概要。リケラボ論文検索は、全国の大学リポジトリにある学位論文・教授論文を一括検索できる論文検索サービスです。

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高濃度酸素性肺障害および新生児慢性肺疾患における肺内代謝および修復に関する研究

田中, 広輔 東京大学 DOI:10.15083/0002007048

2023.03.24

概要

[課程-2]
審査の結果の要旨
氏名 田中 広輔
本研究は、酸素曝露に伴う肺障害に関する研究として、以下の2点を解析したものである。
① 新生仔と成獣のマウスの高濃度酸素曝露に対する感受性の違いに関して、高濃度酸素曝
露後のマウス肺を用いたメタボローム解析を行い、代謝経路という観点からその機序を明
らかとする。② 新生児慢性肺疾患動物モデルにおいて網羅的遺伝子発現解析アレイを行い、
酸素曝露後回復期に肺内で発現変化を示す遺伝子を同定する。さらに、同定されたヒアルロ
ン酸プロテオグリカン結合タンパク質1(Hyaluronan And Proteoglycan Link Protein 1:

Hapln1)遺伝子の高濃度酸素性肺傷害・修復過程における果たす役割および機能を調べる。
これらの解析により下記の結果を得ている。
1.高濃度酸素曝露により成獣マウスの肺において 3-PG、2-PG、PEP、lactic acid など
の解糖に関連する特定の代謝物が増加するが、新生仔マウスの肺においては同様の反応は
見られない。成獣マウスの肺におけるこれらの代謝物レベルの増加は、ピルビン酸脱水素
酵素(pyruvate dehydrogenase : PDH)の負の調節因子であるピルビン酸脱水素酵素キナ
ーゼ 4(pyruvate dehydrogenase kinase 4 : Pdk4)の高濃度酸素曝露による発現上昇に伴
い PDH の酵素活性が低下が関連していると考えられる。
2.新生児慢性肺疾患マウスモデルを用いた網羅的遺伝子発現解析アレイにより、高濃度
酸素曝露直後から修復期にかけて肺において高発現となる Hapln1 遺伝子を同定した。
Hapln1 遺伝子は新生仔マウス肺において酸素曝露により上昇し、曝露終了後も 10 日間以
上高値が持続する。Hapln1 遺伝子欠損マウスの肺は気道・肺胞嚢内腔が狭く実質および
間質が密であり、肺内ヒアルロン酸およびコラーゲン含有量が多い特徴を有する。Hapln1
遺伝子欠損マウスの肺では Saa3、Cxcl1 といった炎症に関わる遺伝子の発現が低下する。
これらの結果より、Hapln1 は、線維芽細胞の増殖および筋線維芽細胞への変換の調節を
介するか、あるいはより直接的な形で BPD における炎症や線維化を制御する役割を担っ
ているのではないかと推測される。
以上、本論文は、新生仔と成獣のマウスの高濃度酸素曝露に対する感受性の違いについ
て、解糖系に関わる代謝の変化における違いが関連している可能性を示した。また、新生
児慢性肺疾患の病態に関わる遺伝子として Hapln1 を同定し、同遺伝子欠損マウスの表現
型解析を通して新生児慢性肺疾患における役割を推測した。高濃度酸素性肺障害および新
生児慢性肺疾患の病態の理解、今度の治療戦略に重要な貢献をなすと考えられる
よって本論文は博士(医学 )の学位請求論文として合格と認められる。

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