JP2016105097A - ニューロン損傷診断のためのマイクロrna、自己抗体およびタンパク質マーカー - Google Patents
ニューロン損傷診断のためのマイクロrna、自己抗体およびタンパク質マーカー Download PDFInfo
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Abstract
Description
本願は、2009年9月14日に出願された米国特許仮出願第61/242,123号、2010年6月14日に出願された同第61/354,504号、2010年6月17日に出願された同第61/355,779号および2010年9月3日に出願された同第61/380,158号に対する優先権を主張するものであり、上記各明細書はその内容全体が本明細書に組み込まれる。
本発明の実施の際に使用する試薬の具体例としては、炭酸水素ナトリウム(Sigma カタログ番号:C−3041)、ブロッキング緩衝液(Startingblock T20−TBS)(Pierce カタログ番号:37543)、Tween20を含むトリス緩衝生理食塩水 (TBST;Sigma カタログ番号:T−9039)、リン酸緩衝生理食塩水(PBS;Sigma カタログ番号:P−3813);Tween20(Sigma カタログ番号:P5927);Ultra TMB ELISA(Pierce カタログ番号:34028);およびNunc maxisorp ELISAプレート(Fisher)が挙げられる。モノクローナルおよびポリクローナルのGFAPおよびUCHL1抗体は、自社製またはSanta Cruz Biotechnology、Santa Cruz、CAから入手したものである。αIIスペクトリン、GFAPおよび分解産物、ならびにMAP2、MBP、ニューロファシン、IgGおよびIgMに対する抗体は、Santa Cruz Biotechnology、Santa Cruz、CAから入手可能である。
抗バイオマーカー特異的ウサギポリクローナル抗体およびモノクローナル抗体ならびに抗原を研究室で作製するか、または市販のものを購入する。標的バイオマーカーを検出するための抗体の反応特異性を判定するために、既知量の単離されたまたは部分的に単離されたバイオマーカーを解析するか、または組織パネルをウエスタンブロットによりプローブする。ELISAプレートに結合させた組換えバイオマーカータンパク質による間接ELISAを用いて、アッセイで使用する抗体の最適濃度を決定する。マイクロプレートをウサギポリクローナル抗ヒトバイオマーカー抗体でコーティングする。最大シグナルのウサギ抗ヒトバイオマーカー抗体濃度を決定した後、間接ELISAの検出下限を各抗体に関して決定する。適当な希釈試料を、ウサギポリクローナル抗ヒトバイオマーカー抗体と2時間インキュベートし、次いで洗浄する。次いで、ビオチン標識モノクローナル抗ヒトバイオマーカー抗体を加え、捕捉されたバイオマーカーとインキュベートする。十分に洗浄した後、ストレプトアビジン西洋ワサビペルオキシダーゼコンジュゲートを加える。1時間のインキュベーションおよび最後の洗浄段階の後、残ったコンジュゲートを過酸化水素テトラメチルベンザジンの基質と反応させる。酸性溶液の添加により反応を停止させ、得られた黄色反応産物の吸光度を450メートルで測定する。吸光度はバイオマーカーの濃度に比例する。較正物質試料を用いて、吸光度値をバイオマーカー濃度の関数としてプロットすることにより標準曲線を作成し、この標準曲線を用いて未知試料の濃度を決定する。
制御式皮質衝撃(CCI)装置を用いて、既に記載されている通りにラットでTBIモデルを作製する(Pikeら,1998)。成体雄(280〜300g)Sprague−Dawleyラット(Harlan:Indianapolis、IN)を、1:1O2/N2Oのキャリヤガス中4%のイソフルランで麻酔し(4分)、同じキャリヤガス中2.5%のイソフルランで維持する。中核体温を直腸内サーミスタプローブにより継続的にモニターし、ラットの下に調節可能な温度制御式加温パッドを敷いて37±1℃に維持する。ラットを腹臥位で定位フレームに載せ、耳棒および切歯棒で固定する。正中頭蓋切開および軟組織反転を行った後、ブレグマとラムダの中間部分、中央縫合のすぐ横で片側(衝撃部位と同側)開頭(直径7mm)を行う。皮質を覆う硬膜はそのままにしておく。直径5mmのアルミニウム製インパクタ先端部(空気圧シリンダー内に収納されている)を用いて、圧縮1.6mmおよび休止時間150ms、3.5m/秒の速度で右側(同側)皮質に衝撃を与えて脳外傷を生じさせる。偽損傷コントロール個体には同じ外科処置を行うが、衝撃損傷は与えない。適切な損傷前および損傷後を行って、Florida大学の動物管理使用委員会(Institutional Animal Care and Use Committee)記載のガイドラインおよび実験動物の管理と使用に関する指針(Guide for the Care and Use of Laboratory Animals)で詳述されている米国国立衛生研究所ガイドラインを確実に遵守する。さらに、動物および動物実験に関連した動物福祉法(Animal Welfare Act)ならびにその他の連邦の制定法および規制に従って、また「Guide for the Care and Use of Laboratory Animals,NRC Publication,1996年版」に記載されている原則に忠実に従って研究を行う。
イソフルラン麻酔(導入チャンバを介した5%イソフルラン、次いでノーズコーンを介した2%イソフルラン)の下で温置し、正中頸部切開によりラットの右側総頸動脈(CCA)を外頸動脈および内頸動脈(ECAおよびICA)分岐レベルで露出させる。ICAを吻側に翼口蓋部の分岐までたどり、ECAを結紮して、その舌部および上顎部の分岐を切る。次いで、ECA断端の切開部分から3−0ナイロン縫合糸をICAに挿入し(血管壁を通して縫合糸の進路を視覚的に監視する)、前大脳動脈の狭窄部で詰まり中大脳動脈の起点を塞ぐまで、頸動脈管内を頸動脈分岐から約20mm進める。次いで皮膚の切開を閉じ、血管内の縫合糸を所定の位置で30分または2時間放置する。ラットを短時間、再び麻酔した後、縫合糸を引き抜いて再灌流させる。偽MCAO手術では、同じ手順に従うが、糸は内外頸動脈分岐から10mmだけ進め、ラットを屠殺するまで所定の位置に放置する。すべての外科的処置の間、保温毛布(Harvard Apparatus、Holliston、MA、U.S.A.)でマウスを37±1℃に維持した。各実験の終わりに、ラット脳が剖検時に、くも膜下出血の病理学的証拠を示した場合、それを実験から除外することに留意することが重要である。適切な損傷前および損傷後の管理を行って、動物の管理と使用のガイドラインをすべて確実に遵守する。
損傷後の適当な時点(2、6、24時間および2、3、5日)でマウスを麻酔し、断頭により直ちに屠殺する。脳を素早く取り出し、氷冷PBSで洗浄して二等分する。右半球(衝撃部位周辺の大脳皮質および海馬)を素早く解剖し、氷冷PBSで洗浄し、液体窒素で急速凍結させ、使用するまで−80℃で保管する。免疫組織化学用に、脳を乾燥氷スラリーで急速に凍結させ、SUPERFROST PLUS GOLD(登録商標)(Fisher Scientific)スライド上にクリオスタットで切片(20μm)を作製し、次いで使用するまで−80℃で保管する。左半球では、右側と同じ組織を採取した。ウエスタンブロット解析用に、脳試料を乾燥氷上で小型の乳鉢と乳棒のセットを用いて微粉末に粉砕する。次いで、粉砕した脳組織粉末を、50mMトリス(pH7.4)、5mM EDTA、1%(v/v)TritonX−100、1mM DTT、1×プロテアーゼインヒビターカクテル(Roche Biochemicals)の緩衝剤中、4℃で90分間、溶解させた。次いで、脳ライセートを4℃で5分間、15,000×gで遠心分離して清澄化し、不溶性の残骸を除去して、急速凍結させ、使用するまで−80℃で保管する。
実施例3に記載のラットでのCCIの後、実施例5の通りにCSFを調製する。抗GFAP抗体を用いたウエスタンブロット法により、CCI損傷後に経時的なGFAPの増加が明らかになっている(図1A、1B)。同様に、GFAPのレベルがCCI後に経時的に増加し、損傷後14日目に統計的に有意な最大レベルとなる(図1C)。ラット同側皮質におけるGFAPおよびGBDPのレベルも測定し、偽(1つまたは複数)処置個体に比べて増加したレベルが示される(図2)。これらのデータは、重度TBIと同様の、CCI後のCSFおよび神経組織におけるGFAPおよびGBDPの増加を示している。
調査には、重度外傷性脳損傷を有する46例のヒト対象が含まれていた。各対象は、年齢が19歳以上、GCSが8以下であり、かつ日常的な治療の一部として脳室フィステル形成術および神経モニタリングが必要であることを特徴とする。詳細にはCSFコントロールと同義であるコントロール群Aには、同様に19歳以上でかつ損傷を有さない10人が含まれていた。水頭症または髄膜炎の治療に関連した日常的な外科的処置またはCSF入手のための脊椎麻酔の際に試料を採取する。正常コントロールと同義として表されるコントロール群Bは、それぞれ18歳以上でかつ脳損傷を伴わない複数の損傷を経験している合計64人であった。調査の人口動態に関するさらなる詳細を表9に記載する。
重度TBI後、対象の血液中でニューロンタンパク質に対する自己抗体が産生され、で検出可能となる。ヒトTBI対象から死後に脳ライセートを入手し、20mMトリス−HCl、pH7.4、150mM NaCl、5mM EDTA、5mM EGTA、1%TritonX−100、1mM NaF、1mM Na3VO4およびプロテアーゼインヒビターカクテルタブレット(Roche、Indianapolis、IN)を含有する溶解緩衝液で可溶化する。SDS−PAGEによりライセートを分離し、次いで全タンパク質に関して染色し(図16A)、プロービングのためにポリフッ化ビニリデン(PVDF)膜(Bio−Rad Laboratories)上に転写する。ヒトコントロールドナーから採取(B)またはTBI10日後にヒトから採取(C)した血清を用いてブロットをプローブし、抗IgG/IgMを用いて自己抗体を検出する。TBI後の対象由来の血清では、血清自己抗体の存在を示す強いバンドが観察される。
TBI後の様々な時点でヒト対象から血清試料を採取する。表10は、3つの異なるTBI相:急性+亜急性相(損傷〜10日目);重度TBI亜急性相(1日目〜30日目);および重度TBI慢性相(TBI後1ヶ月超)で試料を得た患者数を示す。
自己抗体の存在と生存率との相関を解析するために、TBIと診断されたヒト対象の調査をさらに行う。重度(GCIスコアが3〜5)または軽度(GCIスコアが6〜15)TBIを有する20例のヒト対象から血清試料を採取する。表11は、調査対象の特徴を示す。
臓器または脳損傷後にタンパク質がCSFおよび血漿区画に侵入するのと同様に、RNAおよびDNAも侵入する。アポトーシスまたは壊死を起こしている細胞は、血液またはCSF中に核酸バイオマーカーを放出する(図34)。損傷の重症度および部位は、細胞タイプに特異的なRNA量を定量化する適当なリアルタイムPCRアッセイにより特定できる。神経特異的RNAの例としては、βIIIチューブリン、UCHL1、GFAPおよびシナプトフィジンが挙げられる。
TBIの1日後のヒト血清において、ヒトのTBIに関連したmiRNAの存在を検出する。血清を採取し、3000×gで15分間遠心分離し0.2マイクロメートルフィルターを通過させて無細胞とし、全RNAの調製に使用する。全RNA(5μg)を、YM−100 Microcon遠視分離フィルター(Millipore)を用いてサイズ分画する(b300ヌクレオチド)。回収した低分子RNA(b300nt)を、ポリ(A)ポリメラーゼを用いてポリ(A)テールで3’延長する。後の蛍光色素染色のために、オリゴヌクレオチタグをポリ(A)テールに連結する。低分子RNAを一晩、マイクロ循環ポンプを用いてμParafloマイクロ流体チップ上でハイブリダイズさせる(Atactic Technologies)。チップ上の各検出プローブは、標的ヒトmiRNA配列に相補的な化学修飾したヌクレオチドコードセグメントからなる。
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JP2013504331A (ja) | 2013-02-07 |
AU2010291933B2 (en) | 2016-09-08 |
CA2774173A1 (en) | 2011-03-17 |
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US20130022982A1 (en) | 2013-01-24 |
WO2011032155A2 (en) | 2011-03-17 |
AU2016269481B2 (en) | 2018-08-30 |
WO2011032155A3 (en) | 2011-10-06 |
ES2687469T3 (es) | 2018-10-25 |
JP2017181518A (ja) | 2017-10-05 |
AU2010291933A1 (en) | 2012-05-10 |
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