JP5980116B2 - カテプシンhの使用 - Google Patents
カテプシンhの使用 Download PDFInfo
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- JP5980116B2 JP5980116B2 JP2012526071A JP2012526071A JP5980116B2 JP 5980116 B2 JP5980116 B2 JP 5980116B2 JP 2012526071 A JP2012526071 A JP 2012526071A JP 2012526071 A JP2012526071 A JP 2012526071A JP 5980116 B2 JP5980116 B2 JP 5980116B2
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- cathepsin
- compound
- pain
- expression
- protein
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Description
et.Al.,BioTechniques,2006より得られる。
疼痛、好ましくは神経障害性疼痛を調節及び/又は予防する化合物を同定又は分析する方法であって、以下:
a.少なくとも2つの試料を備える工程;
b.カテプシンH又はその機能的フラグメント若しくは誘導体を含む1つの試料を化合物と接触させる工程;
c.化合物の存在下でカテプシンHの活性を測定する工程;
d.化合物の非存在下でカテプシンHの活性を測定する工程;及び
e.c)によるカテプシンHの活性をd)によるカテプシンHの活性と比較する工程;を含む方法。
a.カテプシンHタンパク質又はその機能的フラグメント若しくは誘導体を、試験化合物と接触させる工程;及び
b.その試験化合物がカテプシンHタンパク質又はその機能的フラグメント若しくは誘導体の活性を調節するかどうかを測定する工程;
を含む方法。
a.検出可能な量又は活性のカテプシンH又はその機能的フラグメント若しくは誘導体を有する細胞を、試験化合物と接触させる工程;
b.その試験化合物が細胞中に存在するカテプシンH又はその機能的フラグメント若しくは誘導体の量又は活性を調節できるかどうかを測定する工程;
を含む方法。
a.カテプシンHタンパク質又はその機能的フラグメント若しくは誘導体をコードする核酸を、転写活性のあるシステム中で試験化合物と接触させる工程;及び
b.前述の化合物の存在下で、前述のシステム内に存在するカテプシンHタンパク質又はその機能的フラグメント若しくは誘導体をコードするmRNAの量を測定する工程;及び
c.その化合物が、前述のシステム中に存在するカテプシンHタンパク質又は機能的フラグメント若しくは誘導体をコードするmRNAの量を調節できるかどうかを測定する工程;
を含む方法。
a.レポーター遺伝子又はその機能的フラグメントと作動的にカップリングしたカテプシンH遺伝子又はその機能的フラグメントのプロモータを含む核酸ベクターでトランスフェクトされた細胞を備える工程;
b.機能的カテプシンHプロモータと作動的にカップリングしていないレポーター遺伝子又はその機能的フラグメントを含む対照ベクターでトランスフェクトされた細胞を備える工程;
c.試験化合物の存在下で、a)及びb)による細胞のレポーター遺伝子活性を測定する工程;
d.試験化合物の非存在下で、a)及びb)による細胞のレポーター遺伝子活性を測定する工程;
を含む方法。
a.カテプシンHの活性を調節する化合物を試験化合物として選択する工程;及び
b.該試験化合物を疼痛感覚のある対象に投与し、疼痛が調節されるかどうかを測定する工程;
を含む方法。
c.カテプシンHの生物学的活性を調節する1つ又はそれ以上の調節化合物を同定するために、1つ又はそれ以上の試験化合物の存在下で、カテプシンH又はその機能的フラグメント若しくは誘導体の生物学的活性をアッセイする工程;及び
d.対象における疼痛(好ましくは神経障害性疼痛)、および/または疼痛感覚(好ましくは神経障害性疼痛感覚)、および/または疼痛感受性(好ましくは神経障害性疼痛感受性)を減少させる能力について、1つ又はそれ以上の調節化合物を試験する工程;
を含む方法。
セット1:(ヒトCTSH転写改変体1の検出用の産物長=154ヌクレオチド、ヒトCTSH転写改変体2の検出用の産物長=118ヌクレオチド):
順方向プライマー 5’−GCGCTCCCAGTTGACGCTCT−3’(配列番号10)
逆方向プライマー 5’−CACGCACAGTTCGGCGGC−3’(配列番号11)
セット2:(ヒトCTSH転写改変体1の検出用の産物長= 153ヌクレオチド、ヒトCTSH転写改変体2の検出用の産物長=117ヌクレオチド):
順方向プライマー 5’−CGCTCCCAGTTGACGCTCTGG−3’(配列番号12)
逆方向プライマー 5’−CACGCACAGTTCGGCGGC−3’(配列番号13).
疼痛に悩む対象の疼痛を処置する方法であって、前記対象に治療的有効量の組成物を投与し、前記対象のカテプシンHの量又は活性を低下させることを含む方法。これは、全体又は特定の組織中、例えば、神経組織、リンパ組織又はマスト細胞、マクロファージ、好中球、T細胞(例えばCD8+ T細胞)などのような、免疫システムの細胞中のカテプシンHの量又は活性であればよく、ここで、治療的有効量は、個体の疼痛感覚又は感受性(特に神経障害性疼痛に関する)を回復させるのに十分な量を含む。
使用したマウス系統
5つの異なる近交系マウス系統:AKR/J(AKR)、CBA/J(CBA)、C3H/HeJ(C3H)、C57BL/6J(B6)及び C58/J(C58)を使用した。マウスは、The Jackson Laboratory(Bar Harbor,ME,USA) から入手した。これらのマウス系統について、それらは、幾つかの生体内疼痛指標に関して著しく異なることが示されている(Mogil et al 1999)。
DRG(後根神経節)由来のトータルRNAは、PicoPure(商標)RNA Isolation Kit(Arcturus)を用いて、製造元の使用説明書に従って分離した。RNAの品質は、2100 Bioanalyzer及びRNA 6000 Nano LabChip(商標)Kit(Agilent)を用いて評価した。
ファーストストランドcDNA合成は、Baugh,L.R,Hill,A.A.,Brown,E.L.and Hunter,C.P.(2001) Nucleic Acids Res.29,e29に従って、100pMのT7−(dT)24オリゴマー(GGCCAGTGAATTGTAATACGACTCACTATAGGGAGGCGG−dT24:配列番号14)と共に、500ngのトータルRNA及びSuperScript II逆転写酵素を用い、製造元の説明書の指示に従って行った。二本鎖cDNAを合成し、その後フェノール−クロロホルムを用い、続いてエタノール沈殿工程によって抽出した。生体外転写反応は、二本鎖cDNA試料を用い、BioArray High Yield RNA Transcription Labeling kit(Enzo)を使用して、製造元の使用説明書に従って行った。転写反応は、37℃で16時間インキュベートした。cRNAは、RNA精製用のRNeasy(商標)Mini kit(Qiagen)のプロトコルを用いて精製し、分光光度計で定量した。ビオチン標識cRNAは、RNAフラグメント化緩衝液(200mMのトリス−酢酸、500mMのKOAc、150mMのMgOAc、pH8.1)を用いてフラグメントにした。Mouse Genome 430 2.0 GeneChips(商標)(Affymetrix)のハイブリダイゼーション及び染色は、製造元の使用説明書に従って行った。マイクロアレイは、GeneChip(商標)3000 Scannerを使用して読み取り、読み取ったデータは発現データ分析ソフトResolver v5.1(Rosetta Biosoftware)を用いて取り込み、解析した。
麻酔下のマウスの左L5脊髄神経を露出させ、次に横突起を部分的に除去した。L4脊髄神経から分離した後、L5脊髄神経を切断した。擬似手術は、L5脊髄神経の切断手術と同じであるが、しかしL5脊髄神経は切断しなかった(DeLeo et al.2000を参照)。
足引っ込め限界(PWT)は、動的足底角膜知覚計(dynamic plantar aesthesiometer)を用いて評価した(Szabo et al.2005を参照)。金属網状の床のコンパートメントで馴化した後、刺激装置を動物の後ろ足の下に置き、電動のアクチュエータで駆動するまっすぐな金属の細い線を足底の表面に接触させ、動物が足を取りのけるまで(足引っ込め限界、PWT)上向きに増加する力を与えた。PWTは、同側の、操作された側及び対側部位の後ろ足について評価した。各動物は、1つの測定のみに使用した。すべての動物実験では、意識のある動物による研究に対する倫理ガイドラインを遵守し、その手順は現地倫理委員会によって承認された。
相関関係の解析については、「疼痛表現型」がそれぞれの神経切断動物(Chungの動物)に対してC1−S1として定義され、ここで、C1=ln(同側のPWT/対側のPWT)であり、S1=平均(同一系統内の全擬似動物)ln(同側のPWT/対側のPWT)である。強度発現データに基づいて、差転写調節の2つの単位を、各Chungの動物及び測定した各遺伝子に対して定義した。「生の強度測定」は、それぞれの遺伝子及び動物についての、Resolverの発現データ解析ソフト(v5.1)によって計算された強さの尺度として用いた。「ログ測定比」は、特定の遺伝子及びChungの動物についてln(C2/S2)として計算され、ここで、C2=Chungの発現強度、そしてS2=平均(同一系統内ノ全擬似動物)擬似発現強度である。
疼痛表現型のスコアと転写制御の定義された単位の1つとの間の、各遺伝子についてのピアソンの相関係数は、Rソフトウェアパッケージ(http://www.r−project.org/)を使用して計算した。これらに基づいて、Storey et al.(2002)の方法に従い、統計学的有意性のp値及び対応する偽発見率(FDR)を求めた。「ログ測定比」又は「強度測定」の下でFDR<0.05をもつ遺伝子は、有意に相関していると見なした。
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他に記載がなければ、標準的な実験室手法は以下の標準的な文献に従って行った又は行うことができる。
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他に記載がなければ、実験室手法は下に掲げた標準的な文献の標準的な方法に従って行った、又は行うことができる。
Sambrook et al.(1989) Molecular Cloning:A Laboratory Manual.Second edition.Cold Spring Harbor Laboratory Press,Cold Spring Harbor,NY.545 pp or Current Protocols in Molecular Biology;
Current Protocols in Molecular Biology;regularly updated,e.g.Volume 2000;John Wiley & Sons,Inc;Editors:Fred M.Ausubel,Roger Brent,Robert Eg.Kingston,David D.Moore,J.G.Seidman,John A.Smith,Kevin Struhl.
Current Protocols in Human Genetics;regularly uptdated,e.g.Volume 2003;John Wiley & Sons,Inc;Editors:Nicholas C.Dracopoli,Honathan L.Haines,Bruce R.Korf,Cynthia C.Morton,Christine E.Seidman,J.G.Seigman,Douglas R.Smith.
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Claims (6)
- 神経障害性疼痛感受性を調節する化合物を同定又は分析する方法であって、以下:
a.少なくとも2つの試料を備える工程;
b.カテプシンHを含む1つの試料を化合物と接触させる工程;
c.化合物の存在下でカテプシンHの発現を測定する工程;
d.化合物の非存在下でカテプシンHの発現を測定する工程;及び
e.c)によるカテプシンHの発現をd)によるカテプシンHの発現と比較する工程;を含んでなる、上記方法。 - 神経障害性疼痛感受性を調節する化合物を同定又は分析する方法であって、以下:
a.カテプシンHの検出可能な発現を有する細胞を、試験化合物と接触させる工程;
b.その試験化合物が、細胞中に存在するカテプシンHの発現を調節できるかどうかを測定する工程;
を含んでなる、上記方法。 - 神経障害性疼痛感受性を調節する化合物を同定又は分析する方法であって、以下:
a.カテプシンHタンパク質をコードする核酸を、転写活性のあるシステム中で試験化合物と接触させる工程;及び
b.該化合物の存在下で、該システム内に存在するカテプシンHタンパク質をコードするmRNAの量を測定する工程;及び
c.その化合物が、該システム中に存在するカテプシンHタンパク質をコードするmRNAの量を調節できるかどうかを測定する工程;を含んでなる、上記方法。 - 神経障害性疼痛感受性を調節する化合物を同定又は分析する方法であって、以下:
a.レポーター遺伝子と作動的にカップリングしたカテプシンH遺伝子のプロモータを含む核酸ベクターでトランスフェクトされた細胞を備える工程;
b.機能的カテプシンHプロモータと作動的にカップリングしていないレポーター遺伝子を含む対照ベクターでトランスフェクトされた細胞を備える工程;
c.試験化合物の存在下で、a)及びb)による細胞のレポーター遺伝子活性を測定する工程;
d.試験化合物の非存在下で、a)及びb)による細胞のレポーター遺伝子活性を測定する工程;
を含んでなる、上記方法。 - 神経障害性疼痛感受性を調節する化合物を同定又は分析する方法であって、以下:
a.カテプシンHの発現を調節する化合物を試験化合物として選択する工程;及び
b.該試験化合物を疼痛感覚のある対象(ヒトを除く)に投与し、疼痛が調節されるかどうかを測定する工程;
を含んでなる、上記方法。 - 対象における神経障害性疼痛感受性を調節する化合物を同定又は分析する方法であって、以下:
a.カテプシンHの発現を調節させる1つ又はそれ以上の調節化合物を同定するために、1つ又はそれ以上の試験化合物の存在下で、カテプシンHの発現をアッセイする工程;及び
b.対象(ヒトを除く)における疼痛、疼痛感覚又は疼痛感受性を減少させる能力について、工程aで同定された調節化合物を試験する工程;
を含んでなる、上記方法。
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US6897240B2 (en) * | 2002-05-08 | 2005-05-24 | The Regents Of The University Of California | Thio semicarbazone and semicarbazone inhibitors of cysteine proteases and methods of their use |
US7261882B2 (en) * | 2003-06-23 | 2007-08-28 | Reagents Of The University Of Colorado | Methods for treating neuropathic pain by administering IL-10 polypeptides |
CA2578680C (en) * | 2004-04-15 | 2011-06-14 | University Of Florida Research Foundation, Inc. | Proteolytic markers as diagnostic biomarkers for cancer, organ injury and muscle rehabilitation/exercise overtraining |
EP2105742A1 (en) * | 2008-03-26 | 2009-09-30 | Sanofi-Aventis | Use of cathepsin C |
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CA2772004A1 (en) | 2011-03-03 |
EP2473855A1 (en) | 2012-07-11 |
JP2013502912A (ja) | 2013-01-31 |
US20120252878A1 (en) | 2012-10-04 |
CN102713631A (zh) | 2012-10-03 |
IL218326A0 (en) | 2012-04-30 |
WO2011023786A1 (en) | 2011-03-03 |
AU2010288468A1 (en) | 2012-03-15 |
SG10201507228XA (en) | 2015-10-29 |
KR20120073261A (ko) | 2012-07-04 |
BR112012004450A2 (pt) | 2016-11-16 |
RU2012112539A (ru) | 2013-10-10 |
JP2016104013A (ja) | 2016-06-09 |
EP2293072A1 (en) | 2011-03-09 |
RU2574005C2 (ru) | 2016-01-27 |
AR078002A1 (es) | 2011-10-05 |
TW201113033A (en) | 2011-04-16 |
SG178929A1 (en) | 2012-04-27 |
AU2010288468B2 (en) | 2015-04-30 |
MX346460B (es) | 2017-03-22 |
MY179784A (en) | 2020-11-13 |
CN102713631B (zh) | 2015-12-09 |
IL218326A (en) | 2015-10-29 |
MX2012002627A (es) | 2012-05-08 |
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