JP5701994B2 - シトルリン化タンパク質:生理学的および病理学的疾患のマーカーとしての心筋タンパク質の翻訳後修飾 - Google Patents
シトルリン化タンパク質:生理学的および病理学的疾患のマーカーとしての心筋タンパク質の翻訳後修飾 Download PDFInfo
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Description
本出願は2010年11月12日出願の米国特許仮出願第61/412,819号の優先権を主張し、その全内容は参照により本明細書に組み込まれる。
本出願はEFS−WebによりASCIIフォーマットで提出されている配列表を含有し、参照によりその全体が本明細書に組み込まれる。2011年11月9日作成の前記ASCIIコピーは、22403203.txtと命名され、サイズは7,342バイトである。
本発明は、米国国立衛生研究所により授与されたNHLBIプロテオミクス契約番号NIH N01−HV−28180およびRO1HL63038の政府支援を受けて行われた。米国政府は本発明において一定の権利を有する。
一態様では、本発明は、対象における循環器病を診断する方法であって、対象から得られた生体試料におけるシトルリン化タンパク質の存在を検出することを含む方法を対象とする。別の態様では、ペプチジルアルギニンデイミナーゼ活性の調節も考慮されている。
以下の用語は、他の方法で指示されなければ、以下の本出願全体を通じて定義される通りに使用される。
組織試料:ヒト左心室(LV)経壁組織試料は、末期ISHD、IDCMおよび非不全ドナー心臓を有する患者から得られた。これらの非特定化組織保存試料由来の組織は心停止液中に収集され、液体窒素中で保存された。試料は、Dr.Cris Dos Remoidois、University of Sidney、Australiaにより我々に提供された。本研究ではサブセットが解析される(表2)。
可能になった。CyDyes染色により検出されるスポットは切り取られ、同定に供され
た。全体で、9個のゲル上で最大25個の異なるスポットが検出された。Orbitra
p LTQを使用して、それぞれのスポットのゲル内消化後にペプチドを解析した。全体
で25個のタンパク質スポットのうち、7個のスポットのみが同定に成功した。表4は同
定されたタンパク質を示している。
(1)
対象における循環器病を診断する方法であって、(a)前記対象から生体試料を得ることおよび(b)前記対象から得られた前記生体試料におけるシトルリン化タンパク質の存在を検出することを含み、シトルリン化タンパク質のレベルが循環器病を示している方法。
(2)
前記シトルリン化タンパク質が、前記シトルリン化タンパク質の対照量と比べて上昇している、(1)に記載の方法。
(3)
前記生体試料が、血液、血漿、血清および組織生検からなる群から選択される、(1)に記載の方法。
(4)
前記組織生検が心筋組織である、(2)に記載の方法。
(5)
前記シトルリン化タンパク質が、アルギニン残基からシトルリンへの翻訳後変換を含む、(1)に記載の方法。
(6)
前記シトルリン化タンパク質が、ミオシン重鎖、ミオシン結合タンパク質C、トロポミオシンα1、トロポミオシンα3、アクチン、タイチン、リポタンパク質リパーゼ、L−乳酸デヒドロゲナーゼB鎖、アルファ−1−抗キモトリプシン、カスパーゼ動員ドメイン含有タンパク質10、ジンクフィンガーZZ型およびEF−ハンドドメイン含有タンパク質1からなる群から選択される、(1)に記載の方法。
(7)
前記シトルリン化タンパク質が、配列番号1、配列番号2、配列番号3、配列番号4、配列番号5、配列番号6、配列番号7、配列番号8、配列番号9、配列番号10、配列番号11、配列番号12、配列番号13、配列番号14、配列番号15、配列番号16および配列番号17からなる群から選択されるアミノ酸配列を含む、(1)に記載の方法。
(8)
前記シトルリン化タンパク質が、配列番号19、配列番号20、配列番号21、配列番号22、配列番号23、配列番号24、配列番号25、配列番号26、配列番号27、配列番号28、配列番号29、配列番号30、配列番号31、配列番号32、配列番号33および配列番号34からなる群から選択されるアミノ酸配列を含む、(1)に記載の方法。
(9)
前記シトルリン化タンパク質の存在が、質量分析、高分解能質量分析、タンデム質量分析、結合アッセイ、免疫アッセイ、抗体結合または免疫組織化学を使用して検出される、(1)に記載の方法。
(10)
対象におけるシトルリン化タンパク質に対する自己免疫に対する感受性を診断する方法であって、(a)前記対象から生体試料を得ることおよび(b)前記対象から得られた前記生体試料におけるシトルリン化タンパク質の存在を検出することを含み、シトルリン化タンパク質のレベルが循環器病を示している方法。
(11)
前記シトルリン化タンパク質が、前記シトルリン化タンパク質の対照量と比べて上昇している、(10)に記載の方法。
(12)
前記生体試料が、血液、血漿、血清および組織生検からなる群から選択される、(10)に記載の方法。
(13)
前記組織生検が心筋組織である、(12)に記載の方法。
(14)
前記シトルリン化タンパク質が、アルギニン残基からシトルリンへの変換を含む、(10)に記載の方法。
(15)
前記シトルリン化タンパク質が、ミオシン重鎖、ミオシン結合タンパク質C、トロポミオシンα1、トロポミオシンα3、アクチン、タイチン、リポタンパク質リパーゼ、L−乳酸デヒドロゲナーゼB鎖、アルファ−1−抗キモトリプシン、カスパーゼ動員ドメイン含有タンパク質10、ジンクフィンガーZZ型およびEF−ハンドドメイン含有タンパク質1からなる群から選択される、(10)に記載の方法。
(16)
前記シトルリン化タンパク質が、配列番号1、配列番号2、配列番号3、配列番号4、配列番号5、配列番号6、配列番号7、配列番号8、配列番号9、配列番号10、配列番号11、配列番号12、配列番号13、配列番号14、配列番号15、配列番号16および配列番号17からなる群から選択されるアミノ酸配列を含む、(10)に記載の方法。
(17)
前記シトルリン化タンパク質が、配列番号19、配列番号20、配列番号21、配列番号22、配列番号23、配列番号24、配列番号25、配列番号26、配列番号27、配列番号28、配列番号29、配列番号30、配列番号31、配列番号32、配列番号33および配列番号34からなる群から選択されるアミノ酸配列を含む、(10)に記載の方法。
(18)
前記シトルリン化タンパク質の存在が、質量分析、高分解能質量分析、タンデム質量分析、結合アッセイ、免疫アッセイ、抗体結合または免疫組織化学を使用して検出される、(10)に記載の方法。
(19)
PAD活性の阻害剤を、それを必要とする対象に投与することにより、ペプチジルアルギニンデイミナーゼアイソフォーム1(PAD1)、アイソフォーム2(PAD2)および/またはアイソフォーム4(PAD4)の活性を調節する方法。
(20)
前記阻害剤が、F−アミジン[N−α−ベンゾイル−N5−(2−フルオロ−1−イミノエチル)−1−オルニチンアミド]、2−クロロアセトアミジンおよびCl−アミジン[N−α−ベンゾイル−N5−(2−クロロ−1−イミノエチル)−1−オルニチンアミド]からなる群から選択される、(19)に記載の方法。
Claims (8)
- 対象における虚血性心疾患、心筋症および心不全の診断を補助する方法であって、前記対象から得られた生体試料におけるシトルリン化タンパク質の存在を検出することを含み、シトルリン化タンパク質のレベルがシトルリン化タンパク質の対照量と比べて上昇している場合に虚血性心疾患、心筋症および心不全の可能性を示している方法。
- 前記生体試料が、血液、血漿、血清および組織生検からなる群から選択される、請求項1に記載の方法。
- 前記組織生検が心筋組織である、請求項2に記載の方法。
- 前記シトルリン化タンパク質が、アルギニン残基からシトルリンへの翻訳後変換を含む、請求項1に記載の方法。
- 前記シトルリン化タンパク質が、ミオシン重鎖、ミオシン結合タンパク質C、トロポミオシンα1、トロポミオシンα3、アクチン、タイチン、リポタンパク質リパーゼ、L−乳酸デヒドロゲナーゼB鎖、アルファ−1−抗キモトリプシン、カスパーゼ動員ドメイン含有タンパク質10、ジンクフィンガーZZ型およびEF−ハンドドメイン含有タンパク質1からなる群から選択される、請求項1に記載の方法。
- 前記シトルリン化タンパク質が、配列番号1、配列番号2、配列番号3、配列番号4、配列番号5、配列番号6、配列番号7、配列番号8、配列番号9、配列番号10、配列番号11、配列番号12、配列番号13、配列番号14、配列番号15、配列番号16および配列番号17からなる群から選択されるアミノ酸配列を含む、請求項1に記載の方法。
- 前記シトルリン化タンパク質が、配列番号19、配列番号20、配列番号21、配列番号22、配列番号23、配列番号24、配列番号25、配列番号26、配列番号27、配列番号28、配列番号29、配列番号30、配列番号31、配列番号32、配列番号33および配列番号34からなる群から選択されるアミノ酸配列を含む、請求項1に記載の方法。
- 前記シトルリン化タンパク質の存在が、質量分析、高分解能質量分析、タンデム質量分析、結合アッセイ、免疫アッセイ、抗体結合または免疫組織化学を使用して検出される、請求項1に記載の方法。
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US41281910P | 2010-11-12 | 2010-11-12 | |
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PCT/US2011/060640 WO2012065176A2 (en) | 2010-11-12 | 2011-11-14 | Citrullinated proteins: a post-translated modification of myocardial proteins as marker of physiological and pathological disease |
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US10309974B2 (en) | 2010-11-12 | 2019-06-04 | Cedars-Sinai Medical Center | Citrullinated proteins: a post-translated modification of myocardial proteins as marker of physiological and pathological disease |
US11105817B2 (en) | 2015-06-18 | 2021-08-31 | Cedars-Sinai Medical Center | Role of citrullination in diagnosing diseases |
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US9347941B2 (en) * | 2012-01-13 | 2016-05-24 | Catholic University Industry-Academic Cooperation Foundation | Diagnosis kit for rheumatoid arthritis |
WO2014037911A1 (en) * | 2012-09-10 | 2014-03-13 | Koninklijke Philips N.V. | System and method for estimating susceptibility to a medical condition |
ES2792227T3 (es) | 2014-09-26 | 2020-11-10 | Somalogic Inc | Predicción de evento de riesgo cardiovascular y usos de la misma |
KR102009152B1 (ko) | 2018-03-22 | 2019-08-09 | 충남대학교산학협력단 | APE1/Ref-1을 이용한 심근염 진단 및 진행정도 측정방법 |
US20220276257A1 (en) * | 2019-07-22 | 2022-09-01 | Wisys Technology Foundation, Inc. | Modular Chemical Probe For Detection Of Amino Acid Citrulline In Physiological Samples |
KR102529594B1 (ko) * | 2021-06-23 | 2023-05-09 | 재단법인 아산사회복지재단 | 대동맥판막 협착증 진단 및 예후 예측을 위한 바이오마커로서 항-시트룰린화 펩티드 항체의 용도 |
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WO2001047518A1 (en) * | 1999-12-23 | 2001-07-05 | Childrens Hospital Los Angeles Research Institute | Methods of facilitating vascular growth in cardiac muscle and methods for the production of recombinant emap ii |
DE10225574A1 (de) * | 2002-06-10 | 2003-12-18 | Merck Patent Gmbh | Aryloxime |
DK1721162T3 (da) * | 2004-02-27 | 2008-12-15 | Hoffmann La Roche | Fremgangsmåde til at bedömme rheumatoid arthritis ved at måle anti-CCP og serumamyloid A |
US20070148704A1 (en) * | 2005-10-06 | 2007-06-28 | Ursula Klause | Anti-CCPand antinuclear antibodies in diagnosis of rheumatoid arthritis |
GB0803107D0 (en) * | 2008-02-20 | 2008-03-26 | Axis Shield Diagnostics Ltd | Method |
US9063148B2 (en) * | 2008-10-22 | 2015-06-23 | The Henry M. Jackson Foundation For The Advancement Of Military Medicince, Inc. | Immunoassays for citrullinated proteins |
AU2010224175A1 (en) * | 2009-03-10 | 2011-09-29 | Duke University | Predicting coronary artery disease and risk of cardiovascular events |
BR122013006960A2 (pt) * | 2009-03-30 | 2019-10-15 | Nestec S.A. | Peptídeo sintético que é imunologicamente reativo com um anticorpo de proteína anti-citrulinado, seu uso e seu método de identificação, bem como kit compreendendo o referido peptídeo |
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Cited By (2)
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US10309974B2 (en) | 2010-11-12 | 2019-06-04 | Cedars-Sinai Medical Center | Citrullinated proteins: a post-translated modification of myocardial proteins as marker of physiological and pathological disease |
US11105817B2 (en) | 2015-06-18 | 2021-08-31 | Cedars-Sinai Medical Center | Role of citrullination in diagnosing diseases |
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EP2638401A4 (en) | 2014-03-19 |
WO2012065176A2 (en) | 2012-05-18 |
CA2817847A1 (en) | 2012-05-18 |
JP2014503795A (ja) | 2014-02-13 |
EP2638401B1 (en) | 2017-02-15 |
WO2012065176A9 (en) | 2012-07-05 |
CA2817847C (en) | 2018-02-13 |
US20170328915A1 (en) | 2017-11-16 |
US20140308676A1 (en) | 2014-10-16 |
EP2638401A2 (en) | 2013-09-18 |
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