JP7372927B6 - 遺伝子およびタンパク質の発現を検出する生体分子プローブおよびその検出方法 - Google Patents
遺伝子およびタンパク質の発現を検出する生体分子プローブおよびその検出方法 Download PDFInfo
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- 229920002401 polyacrylamide Polymers 0.000 description 1
- 229920001184 polypeptide Polymers 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 238000004393 prognosis Methods 0.000 description 1
- MWWATHDPGQKSAR-UHFFFAOYSA-N propyne Chemical compound CC#C MWWATHDPGQKSAR-UHFFFAOYSA-N 0.000 description 1
- 238000002331 protein detection Methods 0.000 description 1
- 150000003230 pyrimidines Chemical class 0.000 description 1
- 238000012175 pyrosequencing Methods 0.000 description 1
- 239000011535 reaction buffer Substances 0.000 description 1
- 239000002336 ribonucleotide Substances 0.000 description 1
- 125000002652 ribonucleotide group Chemical group 0.000 description 1
- 125000000548 ribosyl group Chemical group C1([C@H](O)[C@H](O)[C@H](O1)CO)* 0.000 description 1
- 238000007841 sequencing by ligation Methods 0.000 description 1
- 125000006850 spacer group Chemical group 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 238000010186 staining Methods 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- RYYWUUFWQRZTIU-UHFFFAOYSA-K thiophosphate Chemical compound [O-]P([O-])([O-])=S RYYWUUFWQRZTIU-UHFFFAOYSA-K 0.000 description 1
- 229940113082 thymine Drugs 0.000 description 1
- 229940035893 uracil Drugs 0.000 description 1
- 239000011534 wash buffer Substances 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
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Description
本出願は、2018年2月12日に出願された米国仮出願第62/629,180号、および2018年11月26日に出願された米国仮出願第62/771,212号の優先権およびそれらの利益を主張する。前述のそれぞれの特許出願の内容は、その全体が参照により本明細書に組み込まれる。
本出願は、EFS-Webを通してASCII方式で提出された配列一覧を含み、その全体が参照により本明細書に組み込まれる。2019年2月1日に作成された前記ASCIIの複製物は、「NATE-037_001WO.txt」と命名され、容量は48.4KBである。
本開示は、既存の配列決定法を用いて、組織中の利用者規定の領域、利用者規定の細胞、および/または細胞内の利用者規定の部分細胞組織でのタンパク質発現および/または核酸発現を同時に多重かつ空間的に検出および定量するためのプローブ、組成物、方法、およびキットに、一部基づいている。
表1.二末端アダプター連結用の順方向プライマー
表2.両末端アダプター連結用の逆方向プライマー
表3.二末端アダプター連結用の順方向プライマー
表4.二末端アダプター連結用の逆方向プライマー
表5.鋳型プライマー伸長法用の一本鎖核酸鋳型
(1)98℃で30秒、10回
(2)98℃で1分、
(3)68℃で1分
(4)72℃で1分
(5)工程(2)~(4)を10回繰返す
(6)72℃で2分
表6.鋳型プライマー伸長法用の順方向プライマー
表7.鋳型プライマー伸長法用の逆方向プライマー
(1)98℃で30秒
(2)98℃で10秒
(3)65℃で30秒
(4)72℃で30秒
(5)工程(2)~(4)を18回繰り返す
(6)72℃で2分
(2)98℃で1分
(3)68℃で1分
(4)72℃で1分
(5)工程(2)~(4)を10回繰り返す
(6)72℃で2分
(1)98℃で30秒
(2)98℃で10秒
(3)65℃で30秒
(4)72℃で30秒
(5)工程(2)~(4)を18回繰り返す
(6)72℃で2分
(1)98℃で30秒
(2)98℃で1分
(3)68℃で1分
(4)72℃で1分
(5)工程(2)~(4)を10回繰り返す
(6)72℃で2分
表8.短プローブハイブリダイズ法用の順方向プライマー
表9.短プローブハイブリダイズ法用の逆方向プライマー
(1)98℃で30秒
(2)98℃で10秒
(3)65℃で30秒
(4)72℃で30秒
(5)工程(2)~(4)を18回繰り返す
(6)72℃で2分
表10.直接PCR法用の順方向増幅プライマー
表11.直接PCR法用の逆方向増幅プライマー
(1)98℃で30秒
(2)98℃で10秒
(3)65℃で30秒
(4)72℃で30秒
(5)工程(2)~(4)を6~10回繰り返す。
(6)72℃で2分
(1)98℃で30秒
(2)98℃で10秒
(3)65℃で30秒
(4)72℃で30秒
(5)工程(2)~(4)を15~24回繰り返す
(6)72℃で2分
表12.標的タンパク質
表13.標的RNA
表14.標的RNA
Claims (21)
- 組織試料からの少なくとも1つの細胞内の少なくとも1つの標的検体の存在量を空間的に検出する方法であって、以下:
(1)組織試料中の少なくとも1つの細胞内の少なくとも1つの標的検体を、少なくとも3つのプローブと接触させ、それにより前記少なくとも1つの標的検体上に前記プローブをタイリングする工程であって、
ここで前記プローブのそれぞれは:
前記少なくとも1つの標的検体に結合する標的結合ドメイン;および
一本鎖識別子オリゴヌクレオチド
を含み、
ここで前記一本鎖識別子オリゴヌクレオチドは、
前記標的結合ドメインに結合した標的検体を識別する固有の核酸配列、
固有の分子識別子を含む核酸配列、
第1の増幅プライマー結合部位、および
第2の増幅プライマー結合部位
を含み、
ここで前記プローブのそれぞれが、前記一本鎖識別子オリゴヌクレオチドと前記標的結合ドメインとの間に光切断性リンカーを含む、工程;
(2)前記光切断性リンカーを切断することができる十分な波長の光で前記組織試料の位置を励起し、それにより前記一本鎖識別子オリゴヌクレオチドを解放させる工程;
(3)工程(2)で励起された前記組織試料の前記位置から、解放された前記一本鎖識別子オリゴヌクレオチドを採取する工程;
(4)採取された前記一本鎖識別子オリゴヌクレオチドを増幅する工程であって、ここで採取された前記一本鎖識別子オリゴヌクレオチドを増幅することが、PCRを実施することを含み、ここで前記PCRを実施することは、第1の増幅プライマー及び第2の増幅プライマーを含み、
ここで前記第1の増幅プライマーは:
第1のフローセル結合部位;
前記識別子オリゴヌクレオチドが解放された前記組織試料の前記特定の位置を識別する第1の核酸配列;および
前記第2の増幅プライマー結合部位に相補的な核酸配列
を含み;
ここで前記第2の増幅プライマーは:
第2のフローセル結合部位;
前記識別子オリゴヌクレオチドが解放された前記試料の前記特定の位置を識別する第2の核酸配列;および
前記第1の増幅プライマー結合部位に相補的な核酸配列
を含む、工程;および
(5)工程(4)で生成された前記増幅産物を配列決定して解放された前記一本鎖識別子オリゴヌクレオチドを識別し、それにより組織試料中の前記少なくとも1つの細胞内の前記少なくとも1つの標的検体の存在量を空間的に検出する工程
を含む、方法。 - 工程(1)が、組織試料中の少なくとも1つの細胞内の前記少なくとも1つの標的検体を少なくとも5つのプローブと接触させることを含む、請求項1に記載の方法。
- 前記フローセル結合部位のうちの少なくとも1つは、配列決定に適するフローセルアダプター配列を含む、請求項1または2に記載の方法。
- 前記フローセル結合部位のうちの少なくとも1つは、P5フローセルアダプター配列を含み、ここで前記P5フローセルアダプター配列は配列番号3に記載の配列を含む、請求項1~3のいずれか1項に記載の方法。
- 前記フローセル結合部位のうちの少なくとも1つは、P7フローセルアダプター配列を含み、前記P7フローセルアダプター配列は配列番号4に記載の配列を含む、請求項1~4のいずれか1項に記載の方法。
- 前記フローセル結合部位のうちの少なくとも1つは、15~40ヌクレオチドを含む、請求項1~5のいずれか1項に記載の方法。
- 前記フローセル結合部位のうちの少なくとも1つは、29ヌクレオチドを含む、請求項6に記載の方法。
- 前記フローセル結合部位のうちの少なくとも1つは、24ヌクレオチドを含む、請求項6に記載の方法。
- 前記標的結合ドメインに結合した前記標的検体を識別する前記固有の核酸配列は、5ヌクレオチド~25ヌクレオチドを含む、請求項1~8のいずれか1項に記載の方法。
- 前記標的結合ドメインに結合した前記標的検体を識別する前記核酸配列は、12ヌクレオチドを含む、請求項1~9のいずれか1項に記載の方法。
- 前記増幅プライマー結合部位のうちの少なくとも1つは、10~40ヌクレオチドを含む、請求項1~10のいずれか1項に記載の方法。
- 前記増幅プライマー結合部位のうちの少なくとも1つは、34ヌクレオチドを含む、請求項11に記載の方法。
- 前記増幅プライマー結合部位のうちの少なくとも1つは、33ヌクレオチドを含む、請求項11に記載の方法。
- 前記増幅プライマー結合部位のうちの少なくとも1つはi7配列を含み、ここで前記i7配列は配列番号1に記載の配列を含む、請求項1~13のいずれか1項に記載の方法。
- 前記増幅プライマー結合部位のうちの少なくとも1つはi5配列を含み、ここで前記i5配列は配列番号2に記載の配列を含む、請求項1~14のいずれか1項に記載の方法。
- 前記識別子オリゴヌクレオチドが解放された前記組織試料の前記特定の位置を識別する前記核酸配列のうちの少なくとも1つは、1~20ヌクレオチドを含む、請求項1~15のいずれか1項に記載の方法。
- 前記識別子オリゴヌクレオチドが解放された前記組織試料の前記特定の位置を識別する前記核酸配列のうちの少なくとも1つは、8ヌクレオチドを含む、請求項16に記載の方法。
- 固有の分子識別子を含む前記核酸配列は、5~20ヌクレオチドを含む、請求項1~17のいずれか1項に記載の方法。
- 固有の分子識別子を含む前記核酸配列は、14ヌクレオチドを含む、請求項18に記載の方法。
- 前記標的結合ドメインは、10ヌクレオチド~70ヌクレオチドを含む、請求項1~19のいずれか1項に記載の方法。
- 前記標的結合ドメインは、35ヌクレオチド~50ヌクレオチドを含む、請求項20に記載の方法。
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US20190249248A1 (en) | 2019-08-15 |
JP2023182807A (ja) | 2023-12-26 |
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CA3090699A1 (en) | 2019-08-15 |
US20220220555A1 (en) | 2022-07-14 |
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