JP6978058B2 - 褥瘡発生予測マーカー及びその使用 - Google Patents
褥瘡発生予測マーカー及びその使用 Download PDFInfo
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- JP6978058B2 JP6978058B2 JP2017561183A JP2017561183A JP6978058B2 JP 6978058 B2 JP6978058 B2 JP 6978058B2 JP 2017561183 A JP2017561183 A JP 2017561183A JP 2017561183 A JP2017561183 A JP 2017561183A JP 6978058 B2 JP6978058 B2 JP 6978058B2
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Description
[1]Interleukin(IL)−1α、Vascular endothelial growth factor(VEGF)−C、Plasminogen activator inhibitor(PAI)−1及びHeat shock protein(HSP)90αからなる群より選択される、褥瘡発生予測マーカー。
[2]IL−1α、VEGF−C、PAI−1又はHSP90αのcDNAを増幅するためのプライマーセット、IL−1α、VEGF−C、PAI−1又はHSP90αのmRNAに特異的にハイブリダイズするプローブ、又はIL−1αタンパク質、VEGF−Cタンパク質、PAI−1タンパク質又はHSP90αタンパク質に対する特異的結合物質、を備える、褥瘡発生予測キット。
[3]患者の対象領域に由来する試料中の、IL−1α、VEGF−C、PAI−1又はHSP90αの発現量を測定する工程を備える、褥瘡発生予測方法。
[4]前記試料が、水、生理食塩水又は緩衝液で湿らせた、極性を有するメンブレンを、患者の対象領域の皮膚に貼付し、所定時間放置後に回収したメンブレン試料であり、IL−1α、VEGF−C、PAI−1又はHSP90αの発現量を測定する前記工程が、前記メンブレン試料中の、IL−1αタンパク質、VEGF−Cタンパク質、PAI−1タンパク質又はHSP90αタンパク質の存在量を測定する工程である、[3]に記載の褥瘡発生予測方法。
[5]IL−1α、VEGF−C又はPAI−1の発現量が対照と比較して増加していた場合に、前記対象領域に褥瘡が発生すると予測する工程を更に備える、[3]又は[4]に記載の褥瘡発生予測方法。
[6]前記対象領域に発赤が認められ、且つHSP90αの発現量が対照と同等である場合に、前記対象領域に褥瘡が発生すると予測する工程を更に備える、[3]又は[4]に記載の褥瘡発生予測方法。
[7]患者由来の血液試料中の、PAI−1タンパク質の存在量を測定する工程と、PAI−1タンパク質の存在量が対照と比較して増加していた場合に、前記患者は褥瘡を発生すると予測する工程と、を備える、褥瘡発生予測方法。
[8]非ヒト動物の皮膚をつまみ、133.322kPaの圧力を6時間印加する工程を含む、褥瘡モデル非ヒト動物の製造方法。
[9]前記非ヒト動物がマウスであり、前記皮膚が背部皮膚である、[8]に記載の褥瘡モデル非ヒト動物の製造方法。
1実施形態において、本発明は、IL−1α、VEGF−C、PAI−1及びHSP90αからなる群より選択される、褥瘡発生予測マーカーを提供する。
1実施形態において、本発明は、IL−1α、VEGF−C、PAI−1又はHSP90αのcDNAを増幅するためのプライマーセット、IL−1α、VEGF−C、PAI−1又はHSP90αのmRNAに特異的にハイブリダイズするプローブ、又はIL−1αタンパク質、VEGF−Cタンパク質、PAI−1タンパク質又はHSP90αタンパク質に対する特異的結合物質、を備える、褥瘡発生予測キットを提供する。
プライマーセットとしては、IL−1α、VEGF−C、PAI−1又はHSP90α遺伝子のcDNAを増幅することができるものであれば特に限定されない。ヒトIL−1α遺伝子のRefSeq IDはNM_000575であり、マウスIL−1α遺伝子のRefSeq IDはNM_010554である。また、ヒトVEGF−C遺伝子のRefSeq IDはNM_005429であり、マウスVEGF−C遺伝子のRefSeq IDはNM_009506である。また、ヒトPAI−1遺伝子のRefSeq IDはNM_000602であり、マウスPAI−1遺伝子のRefSeq IDはNM_008871である。また、ヒトHSP90α遺伝子のRefSeq IDはNM_001017963であり、マウスHSP90α遺伝子のRefSeq IDはNM_010480である。
プローブとしては、IL−1α、VEGF−C、PAI−1又はHSP90α遺伝子のmRNAに特異的にハイブリダイズするものであれば特に限定されない。プローブは、担体上に固定されてDNAマイクロアレイ等を構成していてもよい。
特異的結合物質としては、例えば、抗体、抗体断片、アプタマー等が挙げられる。抗体は、例えば、マウス等の動物に対象タンパク質又はその部分ペプチドを抗原として免疫することにより作製してもよい。あるいは、ファージライブラリー等の抗体ライブラリーのスクリーニング等により作製することもできる。また、抗体断片としては、Fv、Fab、scFv等が挙げられる。上記の抗体又は抗体断片は、ポリクローナルであってもよく、モノクローナルであってもよい。
1実施形態において、本発明は、患者の対象領域に由来する試料中の、IL−1α、VEGF−C、PAI−1又はHSP90αの発現量を測定する工程を備える、褥瘡発生予測方法を提供する。
1実施形態において、本発明は、非ヒト動物の皮膚をつまみ、133.322kPaの圧力を6時間印加する工程を含む、褥瘡モデル非ヒト動物の製造方法を提供する。非ヒト動物としては、特に限定されず、例えば、ネコ、イヌ、ウマ、サル、ウシ、ヒツジ、ブタ、ヤギ、ウサギ、ハムスター、モルモット、ラット、マウス等が挙げられる。
(褥瘡動物モデルの作製)
9週齢のICRマウス(SLCジャパン)を用いて、カテゴリーIの褥瘡動物モデルを作製した。実験は東京大学動物実験委員会によって承認されたプロトコールにしたがって行った。
(褥瘡動物モデルの肉眼による評価)
各群のマウスについて、マウスへの圧力の印加の前、圧力の印加が終了した直後、30分、60分、90分、120分、24時間及び48時間後に、発赤又は紫斑の肉眼による評価を行った。
(褥瘡動物モデルの組織学的な解析)
マウスへの圧力の印加が終了した60分後及び48時間後に皮膚組織を採取し、組織の損傷を評価するための組織学的な解析を行った。
(褥瘡動物モデルの免疫組織化学的な解析)
作製したカテゴリーIの褥瘡動物モデルが、褥瘡の形成に関連する、阻血性障害、再灌流傷害、リンパ系機能障害及び機械的変形の4つの経路による組織の損傷を有しているか否かを検討するために、免疫組織化学的解析を行った。試料としては、実験例3と同様にして作製した各群のマウスの組織切片を用いた。
まず、阻血性障害を評価するためにHIF−1αタンパク質の発現を検討した。図4はHIF−1αタンパク質の発現を免疫染色により検出した代表的な結果を示す写真である。図4中、黒矢印は、HIF−1α陽性の細胞を示す。また、白矢印はHIF−1αタンパク質の核への移行を示す。
続いて、再灌流障害を評価するために8−OHdGの存在を検出した。図5は8−OHdGを免疫染色により検出した代表的な結果を示す写真である。図5中、黒矢印は、8−OHdG陽性の細胞を示す。
続いて、リンパ系機能障害を評価するためにLYVE−1タンパク質を染色した。図6はLYVE−1タンパク質を免疫染色により検出した代表的な結果を示す写真である。図6中、黒矢印は、LYVE−1タンパク質の存在を示す。
(褥瘡動物モデルにおける褥瘡発生予測マーカーの発現の免疫組織化学的な解析)
続いて、発明者らは、実験例3と同様にして作製した各群のマウスの組織切片を用いて、褥瘡発生予測マーカーの発現を免疫染色により検討した。褥瘡発生予測マーカーとして、PAI−1、IL−1α、VEGF−C及びHSP90αタンパク質の発現を検討した。
図8はPAI−1タンパク質の発現を検出した代表的な結果を示す写真である。図8中、黒矢印は、PAI−1陽性の細胞を示す。
図9はIL−1αタンパク質の発現を検出した代表的な結果を示す写真である。図9中、黒矢印は、IL−1α陽性の細胞を示す。
図10はVEGF−Cタンパク質の発現を検出した代表的な結果を示す写真である。図10中、黒矢印は、VEGF−C陽性の細胞を示す。
図11はHSP90αタンパク質の発現を検出した代表的な結果を示す写真である。その結果、いずれのマウスの群の組織においても、HSP90αタンパク質の発現は認められなかった。
(褥瘡動物モデルにおける褥瘡発生予測マーカーの発現のスキンブロッティングによる解析)
スキンブロッティングにより、非侵襲的に褥瘡発生予測マーカーを検出できるか否かを検討した。褥瘡発生予測マーカーとして、PAI−1、IL−1α、VEGF−C及びHSP90αタンパク質の発現を検討した。
図12はPAI−1タンパク質の発現を検討した結果を示すグラフである。その結果、PAI−1タンパク質の発現は、いずれの時間においても有意な差を示さなかった。
図13はIL−1αタンパク質の発現を検討した結果を示すグラフである。図13中、「†」は対照群対6時間圧力を印加したマウスの群でp値が0.05未満であることを示し、「‡」は1時間圧力を印加したマウスの群対6時間圧力を印加したマウスの群でp値が0.05未満であることを示す。
図14はVEGF−Cタンパク質の発現を検討した結果を示すグラフである。図14中、「†」は対照群対6時間圧力を印加したマウスの群でp値が0.05未満であることを示し、「‡」は1時間圧力を印加したマウスの群対6時間圧力を印加したマウスの群でp値が0.05未満であることを示す。
図15はHSP90αタンパク質の発現を検討した結果を示すグラフである。図15中、「‡」は1時間圧力を印加したマウスの群対6時間圧力を印加したマウスの群でp値が0.05未満であることを示す。
Claims (7)
- Interleukin(IL)−1αタンパク質、Vascular endothelial growth factor(VEGF)−Cタンパク質及びPlasminogen activator inhibitor(PAI)−1タンパク質からなる群より選択され、患者の対象領域の皮膚組織切片の免疫染色で検出した発現量が、対照と比較して増加したことが、前記対象領域に褥瘡が発生することを示す、褥瘡発生予測用マーカー。
- IL−1αタンパク質又はVEGF−Cタンパク質からなり、患者の対象領域のスキンブロッティング試料の免疫染色で検出した発現量が、対照と比較して増加したことが、前記対象領域に褥瘡が発生することを示す、褥瘡発生予測用マーカー。
- IL−1αタンパク質、VEGF−Cタンパク質又はPAI−1タンパク質に対する特異的結合物質を備え、患者の対象領域の皮膚組織切片の免疫染色により、IL−1αタンパク質、VEGF−Cタンパク質又はPAI−1タンパク質の発現を検出するように用いられ、検出された前記タンパク質の発現量が、対照と比較して増加したことが、前記対象領域に褥瘡が発生することを示す、褥瘡発生予測用キット。
- IL−1αタンパク質又はVEGF−Cタンパク質に対する特異的結合物質を備え、患者の対象領域のスキンブロッティング試料の免疫染色により、IL−1αタンパク質又はVEGF−Cタンパク質の発現を検出するように用いられ、検出された前記タンパク質の発現量が、対照と比較して増加したことが、前記対象領域に褥瘡が発生することを示す、褥瘡発生予測用キット。
- 患者の対象領域の皮膚組織切片の免疫染色により、IL−1αタンパク質、VEGF−Cタンパク質又はPAI−1タンパク質の発現量を測定する工程を備え、検出された前記タンパク質の発現量が、対照と比較して増加したことが、前記対象領域に褥瘡が発生することを示す、褥瘡発生予測方法。
- 患者の対象領域のスキンブロッティング試料の免疫染色により、IL−1αタンパク質又はVEGF−Cタンパク質の発現量を測定する工程を備え、検出された前記タンパク質の発現量が、対照と比較して増加したことが、前記対象領域に褥瘡が発生することを示す、褥瘡発生予測方法。
- 患者の対象領域のスキンブロッティング試料の免疫染色により、HSP90αタンパク質の発現量を測定する工程を更に備え、前記IL−1αタンパク質又は前記VEGF−Cタンパク質の発現量が、対照と比較して増加し、前記対象領域に発赤が認められ、且つHSP90αタンパク質の発現量が対照と同等であることが、前記対象領域に褥瘡が発生することを示す、請求項6に記載の褥瘡発生予測方法。
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