JP2013178260A - スクリーニング法 - Google Patents
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Abstract
【解決手段】薬剤に対する疾患の感受性と相関するバイオマーカーを同定する方法であって、a)細胞を、i)薬剤、及びii)細胞内タンパク質のレベル又は活性を抑制する化合物に曝露するステップと、b)細胞における表現型についてモニターするステップとを含み、細胞を薬剤単独で処理するときに現れる表現型とは異なる細胞内表現型の出現から、前記タンパク質又はそれをコードする遺伝子を薬剤感受性と相関するバイオマーカーとして同定する方法。
【選択図】なし
Description
a)細胞を
i)薬剤;及び
ii)細胞内タンパク質のレベル又は活性を抑制する化合物
に曝露するステップと、
b)細胞における表現型についてモニターするステップと
を含み、細胞を薬剤単独で処理するときに現れる表現型とは異なる細胞内表現型の出現から、タンパク質又はそれをコードする遺伝子を薬剤感受性と相関するバイオマーカーとして同定する方法が提供される。
i)アクセッション番号NM_002874;NM_002913;NM_002468;NM_002819;NM_005314;NM_002309;NM_002310;NM_002411;NM_002123;NM_002855;NM_016186;NM_000521;NM_002703;NM_002300;NM_002372;NM_016445;及びNM_013352のいずれか1つにおいて列挙される配列を含む、
ii)i)による配列の断片である、
iii)i)又はii)の相補配列を含む、
iv)高度に厳密な条件下で、i)又はii)による核酸分子をハイブリッド形成する、
核酸分子であって、癌などの増殖性疾患、又は細胞の分化若しくは増殖の速度の変化が関与する疾患若しくは病態の診断又は治療に用いる核酸分子を提供する。
i)アクセッション番号NM_002874;NM_002913;NM_002468;NM_002819;NM_005314;NM_002309;NM_002310;NM_002411;NM_002123;NM_002855;NM_016186;NM_000521;NM_002703;NM_002300;NM_002372;NM_016445;及びNM_013352のいずれか1つにおいて列挙される核酸配列がコードするアミノ酸配列を有する、
ii)i)によるタンパク質の断片であって、ただし前記断片が、i)若しくはii)の全長ポリペプチドが有する生物活性を保持する、又はi)若しくはii)のポリペプチドと共通の抗原決定基を有する断片である、
タンパク質であって、癌などの増殖性疾患、又は細胞の分化若しくは増殖の速度の変化が関与する疾患若しくは病態の診断又は治療に用いるタンパク質を提供する。
[実施例]
細胞培養とトランスフェクション
細胞は、10%FCS及び1%ペニシリン/ストレプトマイシン(Gibco社製)を含むDMEM培地(MCF7、U2OS、及びSAOS2細胞)又はRPMI-40培地(A2780細胞)中で培養した。指示通りに、回収前の最終濃度100nMでオリゴフェクタミン(Invitrogen社製)を用いて、U2OS細胞に合成短ヘアピンsiRNA(Dharmacon社製)をトランスフェクトした。
50%エタノール/PBS中、4℃で一晩細胞を固定し、1倍濃度RNAse A及び20ng/mlヨウ化プロピジウムとともに30分間インキュベートした。試料をFACScanフローサイトメーター(BD Bioscience社製)にかけ、CellQuestProソフトウェアを用いて分析した。
マウス異所性受容体(U2OSEcR)を発現するU2OS細胞に、pRetroSuper RNAiライブラリー(Brummelkamp et al, 2002a/b)を感染させた。該ライブラリーの各プールは、ウェル当たり100のsiRNAを含んでいた。細胞の回収に最長72時間をかけることでsiRNAの発現及びノックダウンを可能とした後、細胞をプレートに播種し一晩置いた(プレート当たり細胞40,000個)。次いで、各プレートに、2μl SAHAを加えた(スクリーニング法の前に細胞数とSAHA濃度を決定した)。次いで、18〜30日間にわたり、SAHA及びウイルスライブラリーで共処理したプレートにおいてコロニーが出現するまで、3日ごとにSAHA含有培地を置換した。次いで、コロニーを採取し増殖させ、総ゲノムDNA及び総タンパク質を単離できるようにした(図1)。
溶解緩衝液(100mMトリス[pH8.5]、0.2%SDS、200mM NaCl、及び100μg/mlプロテイナーゼK)を用いて、コロニー細胞からゲノムDNAを分離し、37℃で振とうしながら30分間放置し、DNAを沈殿させた。次いで、溶解物に1容量のイソプロパノールを添加して10mMトリス[pH7.5]中にDNA沈殿物を溶解し、PCRに用いて問題となる遺伝子の同一性の決定を可能にした。PCRは、Expand Long Template PCR System(Roche社製)を用いて実施した。遺伝子挿入物は、以下のプライマーを用いて回収した。pRS順行:5'-CCCTTGGAACCTCCTCGTTCGACC-3'及びpRS逆行:5’-CAGACGTGCTACTTCCATTTGTC-3’。各回のPCRは、1.2%の1倍濃度TBE/アガロースゲルにおいて分析した。次いで、PCR産物の配列を決定し(Lark Technologies社製)、対象となる遺伝子の同定を可能にした。
細胞をPBSで洗浄し、TNN溶解緩衝液(50mMトリス[pH8]、120mM NaCl、0.5% NP-40、1mMジチオスレイトール、及びプロテアーゼ阻害剤)中、4℃で20分間溶解した。抽出物を16,000gで10分間遠心分離し、細胞残屑を除去した。細胞溶解物を標準化し(ブラッドフォード法)、ポンソーS染色で等量のタンパク質添加量を確認した。SDSポリアクリルアミドゲル電気泳動(PAGE,polyacrylamide gel electrophoresis)による変性化の後、Protranニトロセルロース膜に電気転写して総タンパク質を分離し、次いで、抗体により精査した。用いた抗体は、RFC−1、MYD88、LIF、LIFR、及びhnRNPI(サンタクルス、Biotechnology社製)、並びにhHR23B(Biomol社製)であった。増強化学発光試薬(Pierce社製)を用いて、抗体結合を可視化した。
shRNAノックダウンスクリーニング法(Brummelkamp et al, 2002a)は、8,000を超えるヒト遺伝子を標的とするshRNA(pRetroSuperに含まれる)ライブラリーを使用し、各遺伝子につき3つのshRNA表現ベクターを含む。shRNAから産生されるsiRNAは、強力で特異的な遺伝子発現の抑制を誘導し(Brummelkamp et al, 2002a, b)、pRetroSuperを用いるsiRNAの安定的な発現は、長期間にわたる遺伝子発現の抑制を媒介する。これにより、長期のアッセイにおける機能喪失表現型の解析が可能となる。
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Claims (17)
- 薬剤に対する疾患の感受性と相関するバイオマーカーを同定する方法であって、
a)細胞を
i)薬剤;及び
ii)細胞内タンパク質のレベル又は活性を抑制する化合物
に曝露するステップと、
b)細胞における表現型についてモニターするステップと
を含み、細胞を薬剤単独で処理するときに現れる表現型とは異なる細胞内表現型の出現から、前記タンパク質又はそれをコードする遺伝子を薬剤感受性と相関するバイオマーカーとして同定する方法。 - 化合物が核酸である、請求項1に記載の方法。
- 化合物がsiRNAである、請求項1又は2に記載の方法。
- 化合物がタンパク質の発現レベルを低下させる、請求項1〜3のいずれかに記載の方法。
- 化合物がタンパク質の発現をノックアウトする、請求項4に記載の方法。
- 曝露するステップが、薬剤の存在下で細胞をインキュベートするステップを含む、請求項1〜5のいずれかに記載の方法。
- 細胞集団を薬剤に曝露する、請求項1〜6のいずれかに記載の方法。
- 細胞集団を化合物ライブラリーに曝露する、請求項7に記載の方法。
- 化合物ライブラリーがsiRNAライブラリーである、請求項8に記載の方法。
- 化合物ライブラリーがベクター化RNA干渉ライブラリーである、請求項9に記載の方法。
- ライブラリーがウイルスベクター化RNA干渉ライブラリーである、請求項10に記載の方法。
- 1又は複数の細胞を患者から単離する、請求項1〜11のいずれかに記載の方法。
- 薬剤がHDAC阻害剤である、請求項1〜12のいずれかに記載の方法。
- 1又は複数の細胞を薬剤の組合せに曝露する、請求項1〜13のいずれかに記載の方法。
- 1又は複数の細胞の生存又は増殖特性を表現型とする、請求項1〜14のいずれかに記載の方法。
- 疾患を患う個人の、HDAC阻害剤での治療に対する感受性を診断する方法であって、患者由来の組織におけるhHRAD23B、RFC1、MYD88、PTBP1、PPP4R1、LIF、LIFR、SCBGB2A2、HLA−DQB1、PVRL1、SERPA10、HEXB、PPAT、LDHB、MAN2A1、PLECK2、及びSART2がコードするタンパク質のいずれか1つの発現又は活性レベルを評価するステップと、前記発現又は活性レベルを基準レベルと比較するステップとを含み、前記基準レベルと異なるレベルが、HDAC阻害剤での治療に対する、基準状態と比べた感受性の変化を示す方法。
- hHRAD23B、RFC1、MYD88、PTBP1、PPP4R1、LIF、LIFR、SCBGB2A2、HLA−DQB1、PVRL1、SERPA10、HEXB、PPAT、LDHB、MAN2A1、PLECK2、及びSART2がコードするタンパク質のいずれか1つのアセチル化状態を調節することにより、患者における増殖性疾患又は細胞分化若しくは増殖速度の変化が関与する病態を治療する方法。
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