JP2008520200A - 老化関連病状中の老化及び介入におけるdna損傷の役割に関する早期老化マウスモデル - Google Patents
老化関連病状中の老化及び介入におけるdna損傷の役割に関する早期老化マウスモデル Download PDFInfo
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Abstract
Description
「遺伝子」又は「コード配列」は、個々のタンパク質を「コードする」DNA又はRNA領域(転写される領域)を指す。コード配列は、プロモーターなどの適切な制御領域の調節下に置くと、ポリペプチドに転写され(DNA)翻訳される(RNA)。遺伝子は非コードイントロン及びコードエクソンを含むゲノム配列であってよく、相補的DNA(cDNA)配列であってよい。遺伝子は幾つかの動作可能に連結した断片、例えばポリアデニル化部位を含むプロモーター、転写制御配列、5’リーダー配列、コード配列及び3’非翻訳配列などを含み得る。キメラ又は組換え遺伝子は、例えばプロモーターが転写されるDNA領域の一部又は全体とは本来結合していない遺伝子などの、本来通常は見られない遺伝子である。「遺伝子の発現」は、遺伝子がRNAに転写される且つ/或いは活性タンパク質に翻訳されるプロセスを指す。
ゲノム維持システムは、ヌクレオチド切除修復(NER;包括的ゲノムNER(GG−NER)及び転写関連NER(TC−NERを含む)、転写関連修復(TCR)、分化関連修復(DAR)、塩基切除修復(BER)、及び二本鎖切断修復(DSBR)、及びDNA架橋修復(XLR)経路、及び関連DNA損傷耐性、及びシグナル(DT&S)システム、及びそれに関係があるタンパク質を含む。簡潔のために、この部分はここではGM(ゲノム維持)と表す。
包括的ゲノムNERに影響を与える遺伝子の突然変異は癌傾向の表現型を主にもたらし、一方で転写関連修復(TCR)、及び−本発明の一部分としての−DNA損傷誘導型細胞死又は細胞周期停止を予防するためのゲノム保護と関係がある全ての他の機構(前に定義したGM機構)に、特に影響を与える遺伝子の突然変異によって、早期及び増大した老化の表現型が主に生じる。さらに、このようなTCR関連の早期及び増大した老化の表現型は、TCRの欠陥がXpa又はXpcの欠陥と組み合わさった二重突然変異マウスモデルの表現型から明らかであるように、GG−NERの他の欠陥によってさらに助長され得る。本発明は、害されたゲノム維持及び増大した細胞死又は複製老化をもたらし、早期、加速的及び増大した断片的な老化の表現型を生み出す、TCR/XLR/DSBR/DT&S欠陥を有し、Xpa又は他のGM遺伝子の追加的な突然変異を有するか或いは有さない、新たな動物モデルを開発し利用しようと努める。
[実施例]
早老症は、老化の兆候及び症状の早期の発症によって特徴付けられる、多様な組の特発性又は遺伝性疾患を含む。早老症と自然な老化の間の関係は知られていないが、老化の原因を理解し老化プロセスを研究するための実践モデルを開発するのに重要である。しかしながら、早老症は断片的、或いは組織特異的ことが多く、ヒトの老化との直接の比較は不満足なものとなる。転写又はタンパク質レベルでは早老症と自然な老化の間に幾つかの直接比較可能な点が存在するが、(1)、培養細胞の比較はこの2つの間で同様のものとして示される。
XFE1RO患者線維芽細胞の特徴付け。初代皮膚線維芽細胞培養物を、患者の皮膚バイオプシーから樹立した。15%ウシ胎児血清及び抗生物質を補ったHamsF10培地において、細胞を培養した。試験した細胞系統には、C5RO(正常)、XFE1RO(新たなXP−F患者)、XP42RO(軽度のXPを有する典型的なXP−F患者)、並びにXP−C患者及び完全NER欠陥XP−A患者由来の細胞があった。記載したように(54)ヒトテロメラーゼ逆転写酵素(hTERT)を発現する欠陥レトロウイルスを用いた感染によって、細胞系を不死化状態にした。hTERTの発現レベルはRT−PCRによって測定した(55)。細胞の生存は、初代線維芽細胞をUV(UV−C、254nm)に曝した後、或いは不死化線維芽細胞を架橋剤MMCに曝した後に測定し、前に記載したのと同様に(56)クローン増殖を測定した。MEF中でのクローン生存は、3%O2で培養したマウス胚から樹立した初代細胞系を用いて行った(57)。UV損傷後のNER及び転写関連修復に関する能力も、前に記載したのと同様に(56)それぞれ臨時DNA合成(UDS)及びRNA合成の回収データよって測定した。
新奇の早老症及びXPF−ERCC1欠陥を有する患者。
常習的日焼け及び早期老化の病状を有する15歳の年齢の若い男性が我々に照会された(図1;症例報告の補足オンライン資料S1)。彼の光過敏症のために、皮膚線維芽細胞を得て(細胞系XFE1RO)、UV光に対するそれらの感度を、UV光二量体の欠陥NERのためにXPを有する患者由来の細胞のそれと比較した(物質及び方法;補足オンライン資料S2を参照)。XFE1RO細胞は、野生型(wt)細胞より生存の点で、UVに対して6倍を超えて感度が高かった。これは、軽度(XP−C及び−F相補群)を有する患者と重度XP(XP−A)を有する患者由来の細胞の感度の中間であった(図2A)。UV損傷のDNA修復は、UV露出後に細胞中に取り込まれた放射標識3H−チミジンの量(臨時DNA合成即ちUDS)を測定することによって判定した(図2B)。XFE1RO細胞におけるUDSは正常レベルのわずか5%までであった、これはNERが全くない最重度のXP患者(相補群A)よりごくわずかに高い。UV損傷後のRNA合成の回復は、転写関連DNA修復の指標として測定した(図2C)。これもまた、XP−A患者由来のNER欠陥細胞及びCS患者由来の転写関連NER欠陥細胞と同程度に、XFE1RO細胞において非常に影響を受けた。要約するとXFE1RO細胞は、彼の臨床歴がこの診断と一致しなかったという事実にもかかわらず、XPの特徴であるUV誘導型DNA修復のほぼ完全な不在を示した。
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本出願中に述べるように、Xpanull/null/CsbG744ter/G744terマウス(この実施例中では以後Xpa−/−/Csb−/−マウスと呼ぶ)は、これらの遺伝子の1回突然変異と対照的に、生後初期の発育中に重度の成長遅延、脊柱後弯症、運動失調症、及び運動機能不全を示した[4]。我々はWt、Xpa−/−、Csb−/−及びXpa−/−/Csb−/−15日齢マウスの肝臓において機能的ゲノム分析を施用して、根底の分子経路を洞察した。(各遺伝子型の)4つの個々のマウスの肝臓からの全RNAの単離、及びAffymetrixの完全なマウスゲノムアレイ(Affymetrix Aバージョン2.0)とのその後のハイブリダイゼーション後、我々の分析は、重要なことに同腹子対照ではなくXpa−/−/Csb−/−マウスにおいて、IGF−1/GH−R成長シグナル(Gh−r、IGF−1、IGFBP3、IGFBP4)並びに乳腺刺激(PrR)及び甲状腺刺激機能(Dio1及びDio2)と関係がある遺伝子の有意な下方制御を明らかにした(図7)。この顕著な低下は、抗酸化防御応答と関係がある幾つかの遺伝子(Gstt3、Gsr、Sod1、Hmox1、Ephox1)の有意な高発現(図1)、並びにシトクロムP450及びNADPH酸化代謝と関係がある遺伝子の有意な低発現(図7)をさらに伴った。本明細書に示す幾つかの有意に制御された遺伝子の中で、成長ホルモン受容体(Gh−R)、インスリン成長因子1(IGF−1)、IGF結合タンパク質3(IGFBP3)、プロラクチン受容体(PrR)、グルタチオンsトランスフェラーゼ(GSTT3)、ヘメオキシゲナーゼ1(Hmox1)、エポキシドヒドロラーゼ1(Ephox1)及びアポリポタンパク質A4(ApoA4)の発現プロファイルを、リアル−タイムPCRによる検証に施用した(図8)。
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DNA修復障害であるコケイン症候群(CS)は、関連障害である色素性乾皮症(XP)において見られない広範囲の神経異常を含む。網膜症はこれらの特徴の1つであり、定量式に特異的な老化関連状態の発症を研究するための貴重なモデル器官である。CSの目に関する病状は、この疾患の特徴であると考えられる。CSマウスによって示される網膜変性の現象は、正常に老化する個体群中で生じる老化関連の黄斑変性を暗示し、老人のこの疾患に関する貴重なモデルである可能性がある。類似の戦略を哺乳動物における他の老化関連パラメータに実施することができる。
この実施例は、NER/TCR経路の突然変異を示すマウスにおいて、ゲノム維持誘導型症状、特に老化関連症状を阻害する、予防する且つ/或いは遅延させることができる化合物をスクリーニングするための実験設定を示し、それによって本発明による化合物のスクリーニング法の有用性を例示する。
(M)CSB−/−XPA+/−×(F)CSB−/−XPA+/− (M)CSB−/−XPA+/−×(F)CSB+/−XPA−/−
(M)CSB+/−XPA−/−×(F)CSB+/−XPA−/−
(M)CSB+/−XPA−/−×(F)CSB−/−XPA−/−
実施例2は、肝臓のトランスクリプトーム解析を含めたCsbm/mXpa−/−マウスモデルの詳細な表現型の特徴付けを記載し、どのようにDNA修復の欠陥がIGF/GH軸に影響を与え、自然な老化中にも生じる全身応答を誘導するかに関する所与の新しい洞察を有する。これらの動物は、化合物を迅速にスクリーニングするのに優れたモデルとなる。同時に、1つの特定組織中の遺伝子をノックアウトすることによって、老化関連の組織の病状に対する化合物の影響を研究することが可能となる。ここで我々は、Xpa遺伝子の(Cre−リコンビナーゼ仲介型)組織及び時間特異的不活性化を可能にする、条件付きXpaマウスの作製を記載する。組織特異的及び/又は時間依存形式でXpa遺伝子をノックアウトするために、エクソン4をマウスcDNA(合成ポリA配列を含む)、次にヒグロマイシン(HYGRO)選択可能マーカー(図11A)と融合させた、標的構築体を我々は作製している(図11A)。LoxP部位をエクソン3及びHygroマーカーの下流に導入して、cDNA及び選択可能マーカーのCre仲介型切除を可能にし、最終的にエクソン4を欠くXpa対立遺伝子が生じた。条件付きXpa対立遺伝子の不活性化を目に見える状態にするために、我々はLacZ−GFP融合マーカー遺伝子を、スプライス受容体(SA)及びリボソーム内部進入配列(IRES)の前に挿入して、マーカーの転写及び翻訳を可能にした。3リーディングフレームに停止コドンを含みSAとIRESの間に位置した、多数のリーディングフレーム挿入配列(Murfi)は、Hygroマーカー遺伝子からの考えられる読み過ごし転写産物の任意の翻訳を妨げる。
1.Sakai,K.and J.Miyazaki(1997)."A transgenic mouse line that retains Cre recombinase activity in mature oocytes irrespective of the cre transgene transmission."Biochem Biophys Res Commun237(2):318-24.
2.Layher,S.K.and J.E.Cleaver(1997)."Quantification of XPA gene expression levels in human and mouse cell lines by competitive RT-PCR."Mutat Res383(1):9-19.
実施例5に示したのと同様に、我々は条件付きXPAマウスを作製した。このマウスと適切なCre−リコンビナーゼマウスを組み合わせることによって、我々は時間依存形式及び組織特異形式でXPA遺伝子をノックアウトすることができる。以前にMuraiと同僚は、これらの動物において観察した運動失調と一致する小脳中の増大したアポトーシスを観察している。さらに、我々の15日齢Csbm/mXpac/−肝臓のトランスクリプトーム解析によって、非常に似た老化状態の視床下部を含むIGF−1/GHR軸を含めた、全身応答が明らかになった。さらに我々は、これらの動物の網膜中の増大したアポトーシスを発見している。したがって、脳は研究するための完璧な候補組織である。
1.Dragatsis,I.and S.Zeitlin(2000)."CaMKIIalpha-Cre transgene expression and recombination patterns in the mouse brain."Genesis26(2):133-5.
ヒト個体群における老化関連の骨の消失は充分に文書化されている。閉経後の女性では、多数の破骨細胞及びその活性による主要柱骨の加速的消失に、ゆっくりとした連続的な骨消失期が続き、その最中に柱骨の密度が低下し、皮質骨が細くなり、高い骨折の危険をもたらす(1−3)。男性においても、老化関連の骨の消失は存在するがそれほど顕著ではない、何故なら女性における急速な骨の消失の原因であるエストロゲンレベルの低下がないからである。さらに、男性にはより顕著な骨膜付着、即ち骨の外側(骨膜)での骨形成がある(4)。
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19.Chiu,W.S.,J.F.McManus,et al.(2004)."Transgenic mice that express Cre recombinase in osteoclasts."Genesis39(3):178-85.
20.Ovchinnikov,D.A.,J.M.Deng,et al.(2000)."Col2a1-directed expression of Cre recombinase in differentiating chondrocytes in transgenic mice."Genesis26(2):145-6.
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実施例3に示したように、Csbm/mマウスには老化関連の網膜中の光受容体細胞の消失がある。酸化によるDNA損傷がCsbm/mマウスにおける網膜変性と関係があるかどうかを調べるために、我々はCsbm/mマウスの網膜中の酸化によるDNA損傷を含めた、さまざまな型のDNA損傷を誘導することが知られているIR感度を試験した。
マウス突然変異体が老化に関する有効なモデルであるかどうかを示すためには、突然変異体と自然に老化したマウスによって共有される表現型の特徴を列挙し、或いはそうでなければ一組の老化特性を定義し、これらの幾つが突然変異マウスにおいても見られるかを決定しなければならないと提案されてきている(1)。非常に寿命が短いマウスは幾つかの老化関連の特徴を示すが、我々は完全なマウスゲノムに関する手法を実施して、自然に老化するマウスとのその関連性を偏見なく洞察しようと努めた:
Csbm/m/Xpa−/−マウスの肝臓中の発現プロファイルの変化が、自然に老化したマウスにおける発現パターンと類似しているかどうか、且つどの程度類似しているかを調べるために、我々は増大又は低下した発現を有するとして、全ての有意な発現変化(これらのプローブセットは1865の遺伝子を表す)を分類した。我々は次に、16、96及び130週齢の野生型C57Bl/6マウス(n=4)及び8週齢の野生型C57Bl/6マウス(n=4)の完全なマウスゲノムのトランスクリプトームの比較から得たデータセットに対して、このデータセットを重み付けした。この手法は、Csbm/m/Xpa−/−マウス中と同じ方向に変化する16、96及び130週齢の野生型動物中の遺伝子の割合に直接比例する相関係数(ピアソンのr)を割り当てる。注目すべきことに、DNA修復突然変異マウスと16週齢のマウスの間の、類似性を確認することはできなかった(ピアソンのr=−0.26)。重要なことに、我々はCsbm/m/Xpa−/−と96週齢のマウスの間に正の相関関係を確認し(r=0.15)、130週齢の野生型マウス群との比較を行うと実質的にさらに顕著であった(r=0.40、図17の挿入図を参照)。重要なことに、これらの発見は、全てのAffymetrixプローブセット及び検出カットオフ値を超えるシグナルを含む全マウスのトランスクリプトームと同じ手法を我々が施用した時と等しく、したがって如何なる初期の事前選択又は偏見の導入も回避する。実際のデータセットにおいて見られるのと同程度確実にランダムな相関関係を観察する確率を計算することによって、Csbm/m/Xpa−/−マウスと96及び130週齢の野生型マウスの間で観察した類似性が、ランダムな事象であった可能性を排除した(フィッシャーの正確確率検定p≦0.015)。
XFE患者(実施例1参照)及びErcc1−/−マウスモデルは異なる組織セットにおいて早期老化の明らかな徴候を示したが、我々は正常な老化との類似の程度を決定しようとした。Ercc1−/−マウスにおいて観察したゲノム全体の発現の変化は、生理的変化を確認するための広範囲の読み出し値を与え、正常な老化におけるゲノム全体の発現の変化と比較するための強力な基盤を提供する。初期のcDNA及びAffymetrixマイクロアレイ実験は、20日齢(非瀕死状態)Ercc1−/−マウスと2年齢野生型マウス(表2及び3)の転写応答の間の実質的な重複を指摘した。確認のため、及びAffymetrixの完全なマウスのトランスクリプトーム基盤でこれらの発見を広げるために、我々は最初に、野生型対照と比較して増大又は低下した発現変化を有するとして以前に同定した1675個の遺伝子のセットを分類し、4カ月齢及び2.7年齢のマウスの肝臓を2カ月齢の若年成体対照(n=4)の肝臓と対照したときに得た遺伝子と、それらの遺伝子を比較した。この手法は相関係数(ピアソンのr)を割り当て、これはErcc1−/−、4カ月齢及び2.7年齢マウスの間で発現の変化が同じ方向であった遺伝子の割合に比例した。特にこの分析は、Ercc1−/−マウスは4カ月齢のマウスではなく2.7年齢のマウスと顕著な相関度を共有することを明らかにし(ピアソンのr:0.32と0.03、p≦0.05)、年齢及び遺伝的背景の劇的な違いにもかかわらず、遺伝子発現の基本レベルでXPF−ERCC1の欠陥と自然な老化によって引き起こされる早老症間に、強い類似性が存在することを実証した(図18E)。さらに、Ercc1−/−の転写プロファイルと自然に老化したマウスの相関係数が、同じ手法をErcc1−/−マウスの肝臓において有意に過剰に示されたと前に確認した生物学的テーマに限定したとき(表4)、さらに一層顕著であり、ゲノム全体の発現の変化のレベルにおいてErcc1−/−の早老症と自然な老化プロセスの間で確認した応答の共通点を実証した。
Ercc1−/−及びCsbm/m/Xpa−/−動物は、広範囲の部分的な重複、及び異なる早老症の特徴を有する異なるDNA修復欠陥マウスモデルである。表現型の類似性及び違いが遺伝子発現の基本レベルにおいても反映されるかどうか、且つそれがどの程度かを調べるために、我々は前と同じ手法を適用して、以前に同定した1675個の異なる発現をした遺伝子を、同じ形式で得たCsbm/m/Xpa−/−マウスの遺伝子と比較した(原稿添付)。この手法はCsbm/m/Xpa−/−マウスが、Csbm/m又はXpa−/−1回突然変異体(ピアソンのr:それぞれ0.26及び0.31、図18H)より、Ercc1−/−マウスと有意に高い類似性(ピアソンのr:0.65、p<0.05、図18H及び表5)を示すことを明らかにした。重要なことにこれらの発見は、遺伝的背景の違いにもかかわらず(純粋なC57Bl/6と、FVBとのF1ハイブリッド)、Csbm/m/Xpa−/−マウスの完全なマウストランスクリプトームを、Ercc1−/−(ピアソンのr:0.43、p<0.05)、Csbm/m又はXpa−/−1回突然変異同腹子(ピアソンのr:それぞれ0.29及び0.30)のそれと比較したときも同様であり、未修復DNA損傷に対する応答の均一性及び生理的有意が実証された。
1.R.A.Miller,Science310,44(21 october,2005).
2.S.Gupta,Semin Cancer Biol10,161(Jun,2000)
3.Q.Huang et al.,Toxicol Sci63,196(2001)
Claims (25)
- 哺乳動物におけるゲノム維持に関する物質の影響を測定するための方法であって、非ヒト哺乳動物を物質に曝すことにより、前記哺乳動物がDNA修復及びゲノム維持システムの欠損を引き起こす少なくとも1つの突然変異を示し、前記突然変異がDNA損傷の加速的蓄積及び/又は亢進を引き起こすステップと、前記哺乳動物中のゲノム維持に対する物質の影響を測定するステップとを含む、前記方法。
- ゲノム維持に対する影響を哺乳動物における老化関連の表現型パラメータに対する影響によって測定する、請求項1に記載の方法。
- 哺乳動物が2つ以上のDNA修復又はゲノム維持システムの突然変異の組合せを示す、請求項1又は2に記載の方法。
- 老化関連パラメータを生きた哺乳動物又はそれに由来する部分において試験する、請求項1〜3のいずれかに記載の方法。
- 哺乳動物から得てインビトロで培養した細胞又は組織外植片において老化関連パラメータを試験する、請求項1〜4のいずれかに記載の方法。
- DNA修復及びゲノム維持システムの突然変異が、以下のDNA修復システム:二本鎖切断修復(DSBR)、ヌクレオチド切除修復(NER)、転写関連修復(TCR)、塩基切除修復(BER)、DNA架橋修復(XLR)、ミスマッチ修復の1つ又は複数と関係がある遺伝子内に存在する、請求項1に記載の方法。
- DNA損傷の加速的蓄積を引き起こす突然変異が包括的ゲノムヌクレオチド切除修復(GG−NER)と関係がある遺伝子内に存在する、請求項6に記載の方法。
- DNA損傷の加速的蓄積を引き起こす突然変異が転写関連修復(TCR)と関係がある遺伝子内に存在する、請求項1〜7のいずれかに記載の方法。
- 前記突然変異がXpa、Xpb、Xpc、Xpd、Xpe、Xpf、Xpg、Csa、Csb、Ercc1又はTtdaからなる群から選択される遺伝子の突然変異である、請求項1〜8のいずれかに記載の方法。
- 突然変異体がXpb、Xpd又はTtda遺伝子中のヒト硫黄欠乏症育毛発育異常(TTD)を引き起こす対立遺伝子と同等であるか或いはそれと類似している、請求項9に記載の方法。
- 同等であるTTD突然変異が、ヒトXpd遺伝子:G47R、R112H、D234N、C259Y、S541R、Y542C、R601L、R658C、R658H、D673G、R683W、R683Q、G713R、R722W、A725P、Q726ter、K751Q、ヒトXpb遺伝子:T119P及びヒトTtda遺伝子:M1T、L21P、R57terのTTD関連突然変異からなる群から選択される、請求項10に記載の方法。
- 突然変異体がCsa、Csb、Xpb、Xpd、Xpg、Xpf又はErcc1遺伝子中のヒトコケイン症候群(CS)、複合型色素性乾皮症−コケイン症候群(XPCS)、脳−眼−顔−骨格症候群(COFS)又はXPF−ERCC1症候群を引き起こす対立遺伝子と同等であるか或いはそれと類似している、請求項9に記載の方法。
- ヒトコケイン症候群、COFS又はXPCS症候群を引き起こす突然変異が、ヒトCsa遺伝子:CSAnull、Y322ter、ヒトCsb遺伝子:CSBnull、Q184ter、R453ter、W517ter、R670W、R735ter、G744ter、W851R、Q854ter、R947ter、P1042L、P1095R、R1213G、ヒトXpd遺伝子:G602D、G675R、669fs708ter、ヒトXpb遺伝子:F99S、FS740及びヒトXpg遺伝子:R263ter、659terのCS関連突然変異からなる群から選択される、請求項12に記載の方法。
- マウスにおいて加速的老化の表現型をもたらす突然変異体の組合せがCsanull/null/Xpanull/null、Csanull/null/Xpcnull/null、CsbG744ter/G744ter/Xpanull/null、CsbG744ter/G744ter/Xpcnull/null、XpdG602D/G602D/Xpanull/null、XpdR722W/R722W/Xpanull/null、XpdG602D/R722W/Xpanull/nullからなる群から選択される、請求項9に記載の方法。
- 哺乳動物がげっ歯類である、請求項1〜14のいずれかに記載の方法。
- 哺乳動物がマウス、ラット、ウサギ、モルモットからなる群から選択される、請求項15に記載の方法。
- 老化関連パラメータが寿命、周産期ストレスの存続、若年死、脊柱後弯症、骨粗しょう症、体重、体脂肪率、カヘキシー、サルコペニア、脱毛、白髪、神経及び感覚機能障害、筋肉機能、テロメア縮小、骨硬化症、網膜変性症、光受容体細胞の消失、生殖能力レベル、肝機能、腎機能、胸腺退縮、プルキンエ細胞の消失、貧血、免疫機能障害、糖尿病、遺伝子発現パターン、RNA発現レベル、タンパク質発現レベル、代謝産物レベル、及びホルモンレベルからなる群から選択される、請求項1〜16のいずれかに記載の方法。
- 老化関連パラメータが、処理及び未処理試料の細胞、器官、組織、又は生物物質由来の、単離RNAサンプルのマイクロアレイ上でのハイブリダイゼーションパターン(トランスクリプトーム解析)、タンパク質発現(プロテオーム解析)、又は代謝産物プロファイル(メタボローム解析)として遺伝子発現を比較することによって決定される任意の修復若しくはゲノム維持突然変異体由来の細胞、組織又は生物サンプル中で転写及び翻訳される遺伝子のレベルである、請求項17に記載の方法。
- ゲノム維持遺伝子の突然変異が、対応する野生型哺乳動物よりDNA損傷を蓄積しやすい遺伝的背景を示す哺乳動物内に存在する、請求項1に記載の方法。
- 哺乳動物をDNA損傷処理に曝す、請求項1に記載の方法。
- DNA損傷処理がUV照射、X線、γ線、活性酸素種(ROS)、酸化ストレス及びDNA損傷用化合物からなる群から選択される、請求項20に記載の方法。
- DNA損傷用化合物がパラコート、H2O2、ベロマイシン、イルジンS、DMBA、AAF、アフラトキシン、ベンズ(o)ピレン、EMS、ENU、MMS、MNNG、マイトマイシンC、シスプラチナ、ナイトロジェンマスタード、PUVA及びタクソールからなる群から選択される、請求項21に記載の方法。
- 突然変異が、ゲノム維持と関係がある遺伝子をコードする少なくとも1つの遺伝子の発現を機能的に阻害するために使用される、置換、欠失、挿入、制御配列の変化、又はRNA干渉である、請求項1〜22のいずれかに記載の方法。
- 老化現象及び/又はゲノム維持障害若しくは症候群を治療するための、医薬品を製造するためのマンニトールの使用。
- 老化現象及び/又はゲノム維持障害若しくは症候群を治療するための、医薬品を製造するためのプロリンの使用。
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JP5727364B2 (ja) * | 2009-03-30 | 2015-06-03 | 株式会社 資生堂 | 紫外線障害軽減組成物 |
JP2012231786A (ja) * | 2011-04-18 | 2012-11-29 | Kyushu Univ | 標的遺伝子の発現変化による食品機能成分及び医薬品感受性評価方法 |
CN109790993A (zh) * | 2016-10-11 | 2019-05-21 | 三菱电机株式会社 | 空调装置 |
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EP1815245B1 (en) | 2010-04-21 |
CA2586157A1 (en) | 2006-05-18 |
EP2218449A3 (en) | 2011-05-18 |
DE602005020832D1 (de) | 2010-06-02 |
EP2218449A2 (en) | 2010-08-18 |
WO2006052136A2 (en) | 2006-05-18 |
EP1815245A2 (en) | 2007-08-08 |
AU2005302854A1 (en) | 2006-05-18 |
DK1815245T3 (da) | 2010-08-02 |
EP2241884A2 (en) | 2010-10-20 |
ES2344957T3 (es) | 2010-09-10 |
US20090077676A1 (en) | 2009-03-19 |
AU2005302854B2 (en) | 2012-01-12 |
ATE465406T1 (de) | 2010-05-15 |
EP2241884A3 (en) | 2011-02-23 |
WO2006052136A3 (en) | 2006-11-09 |
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