JP2019129843A - 分子イメージングおよび関連する方法 - Google Patents
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- JP2019129843A JP2019129843A JP2019071309A JP2019071309A JP2019129843A JP 2019129843 A JP2019129843 A JP 2019129843A JP 2019071309 A JP2019071309 A JP 2019071309A JP 2019071309 A JP2019071309 A JP 2019071309A JP 2019129843 A JP2019129843 A JP 2019129843A
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Abstract
Description
本出願は、参照により本明細書に組み込まれる、2013年3月6日出願の米国特許仮出願第61/851,276号の利益を主張する。
本発明は、一般に、単一分子、または単一分子の1つ以上のコレクションのイメージングと、イメージングに関連する方法とに関する。
解像度(r)=λ/(2NA) (1)
解像度(r)=0.61λ/NA (2)
解像度(r)=1.22λ/(NA(obj)+NA(cond)) (3)、
ここで「r」は、解像度(2つの目標物間の最小解像可能距離)であり、「NA」は、顕微鏡の開口数に関する一般的な用語であり、「λ」は、イメージング波長であり、「NA(obj)」が対物レンズの開口数に等しく、「NA(cond)」は、集光レンズの開口数である。
以下の材料、機器および一般的な方法は、本発明の方法の諸態様を示すものである。これらは、開示される発明(単数または複数)を決して限定するものではない。
オリゴマー・プローブは、典型的に、然るべきソフトウェア・パッケージ、例えば、www.singlemoleculefish.comにおいてバイオサーチテクノロジーズ(Biosearch Technologies)を通じて利用可能なProbe Designerを用いて設計される。プローブは、自動化されたDNA/RNAシンセサイザー、例えば、Biosearch8700上を含む、任意の適切な方法で合成されてもよい。
細胞試料を調製するための方法の非限定の例は、次の通りである。www.singerlab.org/protocolsにオンラインで公開されたSinger Lab Protocol(シンガーラボ・プロトコル)を参照。
0.5%ゼラチン中のカバーガラス:カバーガラスを0.1N HCl中で20分間煮沸することにより一箱分のカバーガラスを滅菌する。2回蒸留した水(「DDW:doubly distilled water」中でカバーガラスを数回リンスおよび洗浄する。ゼラチン(1.0g)を秤量して200mlのDDWに加える。結果として生じた混合物を攪拌し、温めて溶解を完了する。滅菌したカバーガラスをゼラチン溶液に移して、20分間オートクレーブする。10×PBSストック:500mlの10×PBSに250μLのDEPCを加える。混合物を溶解させるために攪拌し、次にオートクレーブする。1M MgCl2ストック:MgCl2(20.3g)を秤量して、DDWに加える。洗浄溶液(PBSM):100mlの10×PBSストックに5mlの1M MgCl2ストックを加える。結果として生じた混合物をDDWで1Lに希釈する。抽出溶媒(PBST):100mlの10×PBSストックに5mlのTriton X−100を加える。結果として生じた混合物をDDWで1Lに希釈し、静かに攪拌して溶解を完了する。固定液(4% PFA):10mlバイアルの20%パラホルムアルデヒド・ストックに5mlの10×PBSストックを加える。結果として生じた混合物をDDWで50mlに希釈する。
細胞を標準的な条件下で成長させて、ペトリ皿におけるゼラチン化したカバーガラス上に播種する。任意の処理ステップ、例えば、飢餓および刺激を行う。細胞を氷冷PBSMで手短かに洗浄する。細胞を室温においてPBST中で60秒間抽出する。細胞を氷冷PBSMで2回手短かに洗浄する。細胞を室温においてPFA固定液で20分間固定する。細胞を氷冷PBSMで2回手短かに洗浄する。固定済カバーガラスをPBSM中に4℃で使用まで貯蔵する。
洗浄溶液(PBSM):100mlの10×PBSストックに5mlの1M MgCl2ストックを加える。結果として生じた混合物をDDWで1Lに希釈する。プレ/ポストハイブリダイゼーション洗浄液(50%ホルムアミド/2×SSC):250mlホルムアミドに50mlの20×SSCストックを加える。結果として生じた混合物をDDWで500mLに希釈する。プローブ競合溶液(ssDNA/tRNA):50μlの10mg/ml断片化サケ精子DNAに50μlの10mg/ml大腸菌tRNAを加える。ハイブリダイゼーション用バッファー:60μlのDDWに20μlのBSAおよび20μlの20×SSCストックを加える。低塩濃度洗浄溶液(2×SSC):50mlの20×SSCストックに450mlのDDWを加える。核染色溶液(DAPI):100mlの10×PBSストックに50μlの10mg/ml DAPIストック(10mgを1.0mlのDDWに加えることにより固体から調製)を加える。結果として生じた混合物をDDWで1Lに希釈し、振盪してDAPIを溶解させる。封入剤:適切なキットの要素、例えば、Prolongキット(Molecular Probes)を調製するか、または等価な方法を用いる。
カラーコーディングおよび複数の転写物の検出に先立って、ハイブリダイゼーションの検査を行う。転写部位を示すために2つの高輝度色素を用いる。次に、色素の組み合わせを用いて各遺伝子に任意のカラーコードを割り当て、1つずつ検査を行う。固定したカバーガラスを、ピンセットを用いてコプリン・ジャー中に垂直に配置する。固定した細胞を再水和し、室温においてPBSM中で10分間洗浄する。細胞をプレハイブリダイゼーション溶液中で10分間平衡化する。アッセイされることになる標的の異なる組み合わせごとに、一定分量のオリゴヌクレオチド・プローブ混合物をチューブに加える。競合溶液を100倍超でプローブ混合物(単数または複数)に加える。混合物を真空乾燥する。乾燥したペレットを10μlホルムアミドに再懸濁して、チューブを加熱ブロック上に85℃で5〜10分間置き、その後即座に氷上に置く。10μlのハイブリダイゼーション用バッファーを各チューブに加えて、20μlの反応体積を確保する。ガラス・プレートをパラフィルムで包み、反応のための作用空間に充てる。カバーガラスを重ねることなく各体積を覆って配置できるように、各20μlの反応体積を十分遠く離してプレート上に点在させる。カバーガラスをプレハイブリダイゼーション溶液から取り出して、過剰な液体を拭い取る。各カバーガラスを、細胞側を下にしてプレート上に点在するハイブリダイゼーション・ミックス上に置く。反応を封じ込めるために、プレートおよびカバーガラスをパラフィルムの別の層で包む。ハイブリダイゼーション後にカバーガラスを2回洗浄するのに十分な量のプレハイブリダイゼーション溶液とともにプレートを37℃で3時間インキュベートする。カバーガラスの除去を可能にするためにパラフィルムの上部層を除去して下部層を外す。カバーガラスを予熱した洗浄液とともにコプリン・ジャー中に戻して37℃で20分間インキュベートする。洗浄液を変えて、20分間繰り返す。溶液を2×SSCに変えて、室温で10分間インキュベートする。溶液をPBSMに変えて、室温で10分間インキュベートする。溶液を調製したDAPIに変えて、室温で1分間インキュベートし、次にPBSMで洗浄することにより核を対比染色する。PBSMを変えて、取り付けまで室温で保持する。新たに調製した退色防止封入剤を用い、各カバーガラスを細胞側を下にしてスライドガラス上に取り付ける。過剰な液体を拭い取り、スライドを−20℃で保存する。
TOP1(トポイソメラーゼ(DNA)1)の発現をA549細胞におけるFISHによって分析し、SAOシステム(20×)を用いて画像化/定量化した。SAOイメージング条件は、次の通りである、すなわち、500mW主出力(532nm);500ms露出/フレーム。SAO画像の一部を図7に示す。画像は、およそ100個の細胞を含み、mRNAは、画像中に高輝度/白色/緑色ドットとして現れる。画像内の20個の細胞のサンプリングは、次のmRAカウントを示した、すなわち、56;59;58;54;69;60;63;54;74;65;95;52;60;85;66;67;46;36;65;53。図8は、TOP1 mRNAのSAO画像の関心領域の選択を示し、スポット強度および品質に基づく選択処理グラフを含む。
HER2の発現をMCF7細胞(ヒト乳腺癌細胞株)におけるFISHによって分析し、SAOシステム(20×)を用いて画像化/定量化した。SAOイメージング条件は、次の通りである、すなわち、500mW主出力(532nm);500ms露光/フレーム。結果を図9に示す。右上の画像は、100個超の細胞を含み、mRNAは、画像中に高輝度/白色ドットとして現れる。他の画像は、およそ20個の細胞を示す選択部である。20個の細胞のサンプリングは、次のカウントを示した、すなわち、62、61、71、97、74、66、69、48、58、87、37、92、103、80、90、21、37、109、57、122(平均72)。
FKBP5の発現をA549細胞(ヒト肺腺癌細胞株)におけるFISHによって分析した。図10は、標準的な蛍光顕微鏡(60×/1.41 NA0.1油浸)からの2つの画像を示す。「Minus Dex」とラベルされた画像は、24nMデキサメタゾンの添加によるアップレギュレーションより前の細胞(およそ13個の細胞)を示す;画像「Plus Dex」は、8時間にわたる24nMデキサメタゾンの添加後の細胞(およそ14個の細胞)を示す。大きい方の、ほぼ卵形の構造は、細胞核であり、個別の検出分子が核中および周りの高輝度/白色ドットとして示される。図11は、SAOイメージング・デバイス(20×)を備えるシステムを用いた2つの画像(得られた全画像の1/10)を示す。「Minus Dex」とラベルした画像は、24nMデキサメタゾンの添加によるアップレギュレーションより前の細胞(およそ50個の細胞)を示し、画像「Plus Dex」は、8時間にわたる24nMデキサメタゾンの添加後の細胞(およそ50個の細胞)を示す。大きい方の、ほぼ卵形の構造は、細胞核であり、個別の検出分子が核中および周りの高輝度/白色ドットとして示される。
Claims (48)
- 単一分子のイメージングの方法であって、前記方法は、
a)検査試料をプローブに露出するステップであって、前記プローブは、標的分子に特異的に結合する第1の部分と、1つ以上の波長において光と相互作用する1つ以上の化学基の結果として検出可能である第2の部分とを備え、前記プローブは、複合体を提供するために標的分子に結合する、ステップと、
b)前記複合体を前記1つ以上の化学基と相互作用する1つ以上の波長の光に露出するステップと、
c)1つ以上の単一分子の画像を提供するために、前記1つ以上の化学基と相互作用する1つ以上の波長の光の前記相互作用からの結果を検出するステップと、
を備え、
前記画像は、少なくとも1×105μm2の画像化面積にわたって450nmより良好な解像度を保有し、前記画像は、検出設定を何も変更しない単一の検出ステップにおいて得られる、
方法。 - 前記画像は、合成開口光学系を実現するデバイスを備えるシステムを用いて得られる、請求項1に記載の方法。
- 前記標的とされる分子は、mRNA、lncRNA、snRNA、染色体、BrdUを備えるDNA鎖、EdUを備えるDNA鎖、たんぱく質、および小分子からなる標的分子の群から選択される、請求項2に記載の方法。
- 前記化学基は、蛍光性有機色素、量子ドット、インターカレータ蛍光色素および発現可能な蛍光タンパク質からなる蛍光化合物の群から選択された蛍光化合物である、請求項2に記載の方法。
- 前記画像化面積は、少なくとも1×106μm2である、請求項2に記載の方法。
- 単一分子のイメージングの方法であって、前記方法は、
a)検査試料をプローブに露出するステップであって、前記プローブは、標的分子に特異的に結合する第1の部分と、1つ以上の波長において光と相互作用する1つ以上の化学基を含むように変更可能である第2の部分とを備え、前記プローブは、複合体を提供するために標的分子に結合する、ステップと、
b)前記プローブの前記第2の部分を光と相互作用する前記化学基の1つ以上を含むように変更するステップと、
c)前記複合体を前記1つ以上の化学基と相互作用する1つ以上の波長の光に露出するステップと、
d)1つ以上の単一分子の画像を提供するために、前記1つ以上の化学基と相互作用する1つ以上の波長の光の前記相互作用からの結果を検出するステップと、
を備え、
前記画像は、少なくとも1×105μm2の画像化面積にわたって450nmより良好な解像度を保有し、前記画像は、検出設定を何も変更しない単一の検出ステップにおいて得られる
方法。 - 前記画像は、合成開口光学系を実現するデバイスを備えるシステムを用いて得られる、請求項6に記載の方法。
- 前記プローブの前記第2の部分は、クリックケミストリー;ディールス・アルダー反応;シュタウディンガー・ライゲーション;ヒドラゾン・ライゲーション;オキシム・ライゲーション;ネイティブ・ケミカル・ライゲーション;テトラジン・ライゲーション;マレイミド−チオール・ライゲーション;活性エステル−アミン・ライゲーション;カルボジイミド・ホスファート結合;およびカルボキシ結合からなる化学反応の群から選択された化学反応のタイプを用いて変更される、請求項7に記載の方法。
- 前記標的とされる分子は、mRNA、lncRNA、snRNA、染色体、BrdUを備えるDNA鎖、EdUを備えるDNA鎖、たんぱく質、および小分子からなる標的とされる分子の群から選択される、請求項7に記載の方法。
- 前記画像化面積は、少なくとも1×106μm2である、請求項7に記載の方法。
- mRNAのイメージングの方法であって、前記方法は、
a)単一標識オリゴヌクレオチドのセットを提供するために、各オリゴヌクレオチドが単一の蛍光標識を含む、1つ以上のmRNA標的にハイブリダイズすることが可能な多数のオリゴヌクレオチドを得るステップと、
b)試料調製物を得るステップと、
c)オリゴヌクレオチド−mRNAハイブリッド生成物のセットを産出するために、実質的な数の前記単一標識オリゴヌクレオチドが前記細胞内の1つ以上のmRNA標的とハイブリダイズするように、単一標識オリゴヌクレオチドの前記セットが複数の生細胞を含む前記試料調製物と相互作用することを可能にするステップと、
d)合成開口光学系を実現するデバイスを備えるシステムを用いてオリゴヌクレオチド−mRNAハイブリッド生成物の前記セットを検出するステップと、
を備え、
前記デバイスを備える前記システムは、少なくとも1×105μm2の画像化面積にわたって450nmより良好な解像度を提供する
方法。 - 前記画像化面積は、少なくとも1×106μm2である、請求項11に記載の方法。
- 前記視野内のフルオロフォアの密度は、μm当たり1,000分子未満である、請求項11に記載の方法。
- オリゴヌクレオチド−mRNAハイブリッド生成物の前記セットを検出するステップは、単一の検出ステップにおいて生じ、データは、検出設定を何も変更しないで収集される、請求項11に記載の方法。
- 前記mRNA標的は、CCNB1 mRNA、CENPE mRNA、AURKB mRNA、PLK1 mRNA、PLK4 mRNA、TAGLN mRNA、ACTG2 mRNA、TPM1 mRNA、MYH111 mRNA、DES mRNA、EIF1AX mRNA、AR mRNA、HSPD1 mRNA、HSPCA mRNA、K−ALPHA1 mRNA、MLL5 mRNA、UGT2B15 mRNA、WNT5B5 mRNA、ANXA11 mRNA、FOS mRNA、SFRP1 mRNA、FN1 mRNA、ITGB8 mRNA、THBS2 mRNA、HNT mRNA、CDH10 mRNA、BMP4 mRNA、ANKH mRNA、SEP4 mRNA、SEP7 mRNA、PTN mRNA、VEGF mRNA、SRY mRNA、EGR3 mRNA、FoxP1 mRNA、FoxM1 mRNA、TGCT1 mRNA、ITPKB mRNA、RGS4 mRNAおよびBACE1 mRNAからなるmRNAの群から選択される、請求項11に記載の方法。
- lncRNAのイメージングの方法であって、前記方法は、
a)1つ以上のlncRNAプローブを提供するために、各オリゴヌクレオチドが1つ以上の蛍光標識を含む、1つ以上のlncRNA標的にハイブリダイズすることが可能な1つ以上のオリゴヌクレオチドを得るステップと、
b)複数の生細胞を含む試料調製物を得るステップと、
c)プローブ−lncRNAハイブリッド生成物のセットを産出するために、実質的な数の前記プローブが前記細胞内の1つ以上のlncRNA標的にハイブリダイズするように、前記1つ以上のlncRNAプローブが前記試料調製物と相互作用することを可能にするステップと、
d)合成開口光学系を実現するデバイスを備えるシステムを用いてプローブ−lncRNAハイブリッド生成物の前記セットを画像化することによって、プローブ−lncRNAハイブリッド生成物の前記セットを検出するステップと、
を備え、
前記デバイスを備える前記システムは、少なくとも1×105μm2の画像化面積にわたって450nmより良好な解像度を提供する
方法。 - 前記画像化面積は、少なくとも1×106μm2である、請求項16に記載の方法。
- 前記画像化面積内のフルオロフォアの密度は、μm当たり1,000分子未満である、請求項16に記載の方法。
- プローブ−lncRNAハイブリッド生成物の前記セットを検出するステップは、単一の検出ステップにおいて生じ、データは、検出設定を何も変更しないで収集される、請求項16に記載の方法。
- snRNAのイメージングの方法であって、前記方法は、
a)1つ以上のsnRNAプローブを提供するために、各オリゴヌクレオチドが1つ以上の蛍光標識を含む、1つ以上のsRNA標的にハイブリダイズすることが可能な1つ以上のオリゴヌクレオチドを得るステップと、
b)複数の生細胞を含む試料調製物を得るステップと、
c)プローブ−sRNAハイブリッド生成物のセットを産出するために、実質的な数の前記プローブが前記細胞内の1つ以上のsRNA標的にハイブリダイズするように、前記1つ以上のsRNAプローブが前記試料調製物と相互作用することを可能にするステップと、
d)合成開口光学系を実現するデバイスを備えるシステムを用いてプローブ−sRNAハイブリッド生成物の前記セットを画像化することによって、プローブ−sRNAハイブリッド生成物の前記セットを検出するステップと、
を備え、
前記デバイスを備える前記システムは、少なくとも1×105μm2の画像化面積にわたって450nmより良好な解像度を提供する
方法。 - 前記画像化面積は、少なくとも1×106μm2である、請求項20に記載の方法。
- 前記画像化面積内のフルオロフォアの密度は、μm当たり1,000分子未満である、請求項20に記載の方法。
- プローブ−snRNAハイブリッド生成物の前記セットを検出するステップは、単一の検出ステップにおいて生じ、データは、検出設定を何も変更しないで収集される、請求項20に記載の方法。
- 染色体、または染色体の一部のイメージングの方法であって、前記方法は、
a)1つ以上の染色体プローブを提供するために、各オリゴヌクレオチドが1つ以上の蛍光標識を含む、標的染色体内の1つ以上の位置にハイブリダイズすることが可能な1つ以上のオリゴヌクレオチドを得るステップと、
b)複数の生細胞を含む試料調製物を得るステップと、
c)プローブ−染色体ハイブリッド生成物のセットを産出するために、実質的な数の前記プローブが前記細胞内の前記染色体標的内の1つ以上の位置にハイブリダイズするように、前記1つ以上の染色体プローブが前記試料調製物と相互作用することを可能にするステップと、
d)合成開口光学系を実現するデバイスを備えるシステムを用いてプローブ−染色体ハイブリッド生成物の前記セットを画像化することによって、プローブ−染色体ハイブリッド生成物の前記セットを検出するステップと、
を備え、
前記デバイスを備える前記システムは、少なくとも1×105μm2の画像化面積にわたって450nmより良好な解像度を提供する
方法。 - 前記画像化面積は、少なくとも1×106μm2である、請求項24に記載の方法。
- 前記画像化面積内のフルオロフォアの密度は、μm当たり1,000分子未満である、請求項24に記載の方法。
- プローブ−染色体ハイブリッド生成物の前記セットを検出するステップは、単一の検出ステップにおいて生じ、データは、検出設定を何も変更しないで収集される、請求項24に記載の方法。
- 細胞の複製DNA鎖へのBrdUの取り込みを用いた細胞増殖のイメージングの方法であって、前記方法は、
a)複数の生細胞を含む試料調製物を得るステップと、
b)ある量のBrdUを前記試料調製物に供給して、実質的な量の前記BrdUが、増殖している細胞中に取り込まれることを可能にする期間にわたって、前記供給されたBrdUを前記試料調製物とともにインキュベートするステップと、
c)1つ以上の蛍光基を備えるある量の抗BrdU抗体を前記試料調製物に供給して、実質的な量の前記抗体の、前記複製DNA中に取り込まれた前記BrdUへの結合を可能にする期間にわたって、前記供給された抗体を前記試料調製物とともにインキュベートするステップと、
d)合成開口光学系を実現するデバイスを備えるシステムを用いて前記BrdUに結合された抗体を画像化することによって、前記BrdUに結合された抗体を検出するステップと、
を備え、
前記デバイスを備える前記システムは、少なくとも1×105μm2の画像化面積にわたって450nmより良好な解像度を提供する
方法。 - 前記画像化面積は、少なくとも1×106μm2である、請求項28に記載の方法。
- 前記画像化面積内のフルオロフォアの密度は、μm当たり1,000分子未満である、請求項28に記載の方法。
- 前記BrdUに結合された抗体を検出するステップは、単一の検出ステップにおいて生じ、データは、検出設定を何も変更しないで収集される、請求項28に記載の方法。
- 細胞の複製DNA鎖へのEdUの取り込みを用いた細胞増殖のイメージングの方法であって、前記方法は、
a)複数の生細胞を含む試料調製物を得るステップと、
b)ある量のEdUを前記試料調製物に供給して、実質的な量の前記EdUが、増殖している細胞中に取り込まれることを可能にする期間にわたって、前記供給されたEdUを前記試料調製物とともにインキュベートするステップと、
c)ある量の蛍光標識されたアジド系クリック試薬を、前記取り込まれたEdUと前記クリック試薬との間の反応を可能にする条件下で供給するステップと、
d)合成開口光学系を実現するデバイスを備えるシステムを用いて前記EdU−クリック試薬反応生成物を画像化することによって、前記EdU−クリック試薬反応生成物を検出するステップと
を備え、
前記デバイスを備える前記システムは、少なくとも1×105μm2の画像化面積にわたって450nmより良好な解像度を提供する
方法。 - 前記画像化面積は、少なくとも1×106μm2である、請求項32に記載の方法。
- 前記画像化面積内のフルオロフォアの密度は、μm2当たり1,000分子未満である、請求項32に記載の方法。
- 前記EdUに結合された抗体を検出するステップは、単一の検出ステップにおいて生じ、データは、検出設定を何も変更しないで収集される、請求項32に記載の方法。
- 患者における疾患を診断する方法であって、前記方法は、定量的な評価を提供するために、前記疾患と関連付けられた1つ以上の遺伝子の発現を定量的に評価するステップを備え、前記定量的な評価は、前記遺伝子から転写されたmRNAの1つ以上のタイプの検出を備え、イメージングは、少なくとも10個のオリゴヌクレオチド・プローブにハイブリダイズされた単一mRNA分子を備える分子複合体の前記イメージングを備え、前記イメージングは、少なくとも1×105μm2の画像化面積にわたって450nmより良好な解像度で行われる、方法。
- 少なくとも1×106個の別個の分子複合体が画像化される、請求項36に記載の方法。
- 前記1つ以上の遺伝子が関連付けられる前記疾患は、乳癌、大腸癌、前立腺癌、精巣癌、およびアルツハイマー病からなる疾患の群から選択される、請求項36に記載の方法。
- 前記イメージングは、合成開口光学系を実現するデバイスを備えるシステムによって行われる、請求項36に記載の方法。
- 前記mRNAは、CCNB1 mRNA、CENPE mRNA、AURKB mRNA、PLK1 mRNA、PLK4 mRNA、TAGLN mRNA、ACTG2 mRNA、TPM1 mRNA、MYH111 mRNA、DES mRNA、EIF1AX mRNA、AR mRNA、HSPD1 mRNA、HSPCA mRNA、K−ALPHA1 mRNA、MLL5 mRNA、UGT2B15 mRNA、WNT5B5 mRNA、ANXA11 mRNA、FOS mRNA、SFRP1 mRNA、FN1 mRNA、ITGB8 mRNA、THBS2 mRNA、HNT mRNA、CDH10 mRNA、BMP4 mRNA、ANKH mRNA、SEP4 mRNA、SEP7 mRNA、PTN mRNA、VEGF mRNA、SRY mRNA、EGR3 mRNA、FoxP1 mRNA、FoxM1 mRNA、TGCT1 mRNA、ITPKB mRNA、RGS4 mRNAおよびBACE1 mRNAからなるmRNAの群から選択される、請求項36に記載の方法。
- 1つ以上の生細胞内の1つ以上の遺伝子のアップまたはダウンレギュレーションに対するその効果に関して、小または大分子の活性をアッセイする方法であって、前記方法は、
a)前記小または大分子を複数の生細胞を備える細胞試料とともにインキュベートするステップと、
b)前記細胞を透過処理し、前記1つ以上の遺伝子から転写された少なくとも1つのmRNAとハイブリダイズすることが可能な、少なくとも10個の異なるオリゴヌクレオチド・プローブを備える混合物中に前記細胞を浸漬して、オリゴヌクレオチドおよび単一mRNA分子を備える分子複合体の形成をもたらすステップと、
c)前記分子複合体を検出するステップであって、イメージング結果を提供するために、少なくとも1×106μm2の画像化面積にわたって450nm以上の解像度で前記分子複合体を画像化することを備える、ステップと、
d)分析結果を提供するために前記1つ以上の遺伝子の発現を定量化すべく前記イメージング結果を分析するステップであって、前記分析結果は、前記遺伝子のアップまたはダウンレギュレーションを確定することを可能にする、ステップと、
を備える、方法。 - 画像化は、合成開口光学系を実現するデバイスを備えるシステムを用いて行われる、請求項41に記載の方法。
- 少なくとも1×106個の別個の分子複合体が画像化される、請求項41に記載の方法。
- 前記検出するステップは、蛍光顕微鏡を用いて検出が行われる同じ方法より少なくとも5倍速く行われる、請求項41に記載の方法。
- 少なくとも100個の小分子または大分子が同じイメージング・システムを用いて24時間でアッセイされる、請求項41に記載の方法。
- 疾患を有する患者が特定の化学療法に対して良好に反応することになるかどうかを予測する方法であって、前記方法は、定量的な評価を提供するために、前記疾患と関連付けられた1つ以上の遺伝子の発現を定量的に評価するステップを備え、前記定量的な評価は、前記遺伝子から転写されたmRNAの1つ以上のタイプの検出を備え、イメージングは、少なくとも10個のオリゴヌクレオチド・プローブにハイブリダイズされた単一mRNA分子を備える分子複合体のイメージングを備え、前記イメージングは、少なくとも1×106μm2の画像化面積にわたって450nmもしくはより良好な解像度で行われ、前記定量的な評価は、患者が前記特定の化学療法に良好に反応することになるかどうかと相互に関連付けられる、方法。
- 前記疾患は、癌である、請求項46に記載の方法。
- イメージングは、合成開口光学系を実現するデバイスを備えるシステムを用いて行われる、請求項46に記載の方法。
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