JP2008504044A - Gpr86受容体の使用 - Google Patents
Gpr86受容体の使用 Download PDFInfo
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- JP2008504044A JP2008504044A JP2007518705A JP2007518705A JP2008504044A JP 2008504044 A JP2008504044 A JP 2008504044A JP 2007518705 A JP2007518705 A JP 2007518705A JP 2007518705 A JP2007518705 A JP 2007518705A JP 2008504044 A JP2008504044 A JP 2008504044A
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- gpr86
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- polypeptide
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Abstract
【選択図】図5
Description
本発明は、核酸の新しく同定された機能、それによりコードされるポリペプチド、およびその産生と使用に関する。より詳細には、該核酸およびポリペプチドは、以下「GPR86」と言うあるGタンパク質共役型受容体(GPCR)、およびGPCRのプリノセプターファミリーのメンバーに関する。本発明はまた、こうした核酸およびポリペプチドの作用の阻害または活性化にも関する。
多くの医学的に重要な生物学的プロセスは、Gタンパク質および/または第2メッセンジャー、例えばcAMPが関係するシグナル伝達経路に関与するタンパク質により仲介されることはよく知られている(Lefkowitz, Nature, 1991, 351: 353-354)。こうしたタンパク質のことを、Gタンパク質を有する経路に関与するタンパク質、または「PPGタンパク質」と言う。こうしたタンパク質のいくつかの例としては、GPC受容体、例えばアドレナリン作動薬およびドーパミンの受容体(Kobilka, B. K.,ら, Proc. Natl Acad. Sci., USA, 1987, 84: 46-50; Kobilka B. K.,ら, Science, 1987, 238: 650-656; Bunzow, J. R.,ら, Nature, 1988, 336: 783-787)、Gタンパク質それ自体、エフェクタータンパク質、例えばホスホリパーゼC、アデニルシクラーゼ、およびホスホジエステラーゼ、ならびにアクチュエータータンパク質、例えばタンパク質キナーゼAおよびタンパク質キナーゼC (Simon, M. I.,ら, Science, 1991, 252: 802-8)が挙げられる。
Lefkowitz, Nature, 1991, 351: 353-354 Kobilka, B. K., et al., Proc. Natl Acad. Sci., USA, 1987, 84: 46-50 Kobilka B. K., et al., Science, 1987, 238: 650-656 Bunzow, J. R., et al., Nature, 1988, 336: 783-787 Simon, M. I., et al., Science, 1991, 252: 802-8 Johnson et al., Endoc. Rev., 1989, 10: 317-331
本発明の第1の態様において、本発明者らは、GPR86関連疾患、特に炎症性疾患または疼痛の治療、予防または緩和に好適な分子の同定方法であって、候補分子がGPR86ポリペプチドのアゴニストまたはアンタゴニストであるか否かを判別することを含み、ただし前記GPR86ポリペプチドは配列番号3もしくは配列番号5もしくは配列番号7に記載のアミノ酸配列、その断片またはそれに少なくとも90%同一な配列を含む、前記方法を提供する。
(a) 野生型動物または機能破壊された内因性GPR86遺伝子を有するトランスジェニック非ヒト動物を用意すること;
(b) 前記野生型動物またはトランスジェニック非ヒト動物を候補分子に曝露すること;および
(c) 前記動物の生物学的パラメーターが前記接触の結果変化したか否かを測定すること、を含む。
(a) 野生型細胞または機能破壊された内因性GPR86遺伝子を有する細胞、好ましくは機能破壊された内因性GPR86遺伝子を有するトランスジェニック非ヒト動物から単離された細胞を用意すること;
(b) 前記細胞を候補分子に曝露すること;および
(c) GPR86ポリペプチドの生物学的活性が前記接触の結果変化したか否かを測定すること、を含む。
(a) かかる疾患に罹患しているかまたは罹患している疑いのある動物におけるGPR86ポリペプチドの発現レベルまたは発現パターンを検出すること;および
(b) 該発現レベルまたは発現パターンを正常動物のそれと比較すること、
を含む前記方法を提供する。
配列番号1はヒトGPR86のcDNA配列を示す。配列番号2は、配列番号1から誘導されたオープンリーディングフレームを示す。配列番号3はヒトGPR86のアミノ酸配列を示す。配列番号4はマウスGPR86由来のcDNAのオープンリーディングフレームを示す。配列番号5はマウスGPR86のアミノ酸配列を示す。配列番号6は、ヒトGPR86の別のcDNA配列を示す。配列番号7はヒトGPR86の別のアミノ酸配列を示す。配列番号8〜20はノックアウトプラスミドのプライマー配列を示す。配列番号21はノックアウトプラスミドの配列を示す。
本発明の実施には、特に断らない限り、化学、分子生物学、微生物学、組換えDNA技術および免疫学の慣用技術を用いるが、これらは当業者の能力の範囲内にある。こうした技術は刊行物に解説されている。例えば、J. Sambrook, E. F. Fritsch, and T. Maniatis, 1989, Molecular Cloning: A Laboratory Manual, 第2版, 1-3巻, Cold Spring Harbor Laboratory Press; Ausubel, F. M. ら (1995および定期的補完物; Current Protocols in Molecular Biology, 第9, 13, および16章, John Wiley & Sons, New York, N.Y.); B. Roe, J. Crabtree, and A. Kahn, 1996, DNA Isolation and Sequencing: Essential Techniques, John Wiley & Sons; J. M. Polak and James O’D. McGee, 1990, In Situ Hybridization: Principles and Practice; Oxford University Press; M. J. Gait (編者), 1984, Oligonucleotide Synthesis: A Practical Approach, Irl Press; D. M. J. Lilley and J. E. Dahlberg, 1992, Methods of Enzymology: DNA Structure Part A: Synthesis and Physical Analysis of DNA Methods in Enzymology, Academic Press; Using Antibodies : A Laboratory Manual : Portable Protocol NO. I by Edward Harlow, David Lane, Ed Harlow (1999, Cold Spring Harbor Laboratory Press, ISBN 0-87969-544-7); Antibodies : A Laboratory Manual by Ed Harlow (編者), David Lane (編者) (1988, Cold Spring Harbor Laboratory Press, ISBN 0-87969-314-2), 1855, Lars-Inge Larsson “Immunocytochemistry: Theory and Practice”, CRC Press inc., Baca Raton, Florida, 1988, ISBN 0-8493-6078-1, John D. Pound (編); “Immunochemical Protocols, vol 80”, in the series: “Methods in Molecular Biology”, Humana Press, Totowa, New Jersey, 1998, ISBN 0-89603-493-3, Handbook of Drug Screening, Ramakrishna Seethala, Prabhavathi B. Fernandes編集(2001, New York, NY, Marcel Dekker, ISBN 0-8247-0562-9); Lab Ref: A Handbook of Recipes, Reagents, and Other Reference Tools for Use at the Bench, Jane Roskams and Linda Rodgers編集, 2002, Cold Spring Harbor Laboratory, ISBN 0-87969-630-3; およびThe Merck Manual of Diagnosis and Therapy (第17版, Beers, M. H., and Berkow, R, 編, ISBN: 0911910107, John Wiley & Sons)を参照されたい。これらの一般的教材をそれぞれ参照により本明細書に組み入れる。
GPR86
本明細書は、大まかにGタンパク質共役型受容体(GPCR)、特に本発明者らがGPR86と呼ぶプリノセプター型Gタンパク質共役型受容体、ならびにそのホモログ、変異体または誘導体を記載する。
GPR86 cDNAのポリメラーゼ連鎖反応(PCR)増幅により、GPR86の発現はヒト由来組織の骨髄、胸腺、リンパ節、白血球、骨芽細胞および軟骨細胞において種々の量で検出される。該発現は、ヒト由来細胞系Jurkat CD4+およびMyla CD8+(いずれもT細胞由来)にも見られた。低レベルの発現はColo720(リンパ球由来)およびTHP1細胞(単球由来)に見られた(実施例4;図7)。
本明細書に記載の方法および組成物について、GPR86 GPCRはある範囲の疾患の治療および診断に有用である。こうした疾患のことを便宜上「GPR86関連疾患」と言う。
GPR86およびその変異体ならびにそれらをコードする配列、それに対する抗体など本明細書に記載のものを、疼痛に関連する多くの疾患の診断および/または治療に使用することができる。
急性疼痛とは、短期的疼痛または容易に特定できる原因のある疼痛と定義される。急性疼痛は、組織または疾患に対するその時の損傷を体が警告しているものである。急性疼痛は多くの場合、迅速で鋭く、うずく痛みがそれに続く。急性疼痛はある領域に集中しその後いくらか広がる。
慢性疼痛とは6ヶ月以上継続した疼痛と医学的に定義される。この持続性のまたは断続性の疼痛は多くの場合、体が損傷を予防するのを助けないため、時を経てその目的を失っている。慢性疼痛は多くの場合、急性疼痛よりも治療するのが困難である。一般には、あらゆる慢性化してしまった疼痛を治療するには熟練した看護が必要である。長期間オピオイドが使用される場合、薬物耐性、薬物依存症および心理的中毒症さえも生じうる。オピオイド使用者において薬物耐性および薬物依存症は一般的であるが、心理的中毒症は希である。
皮膚疼痛は、皮膚または表面組織への損傷によって引き起こされる。皮膚侵害受容器は皮膚の直ぐ下で終結しており、神経終末の密度が高いことから、明確で局在性の短期間の疼痛が生じる。皮膚疼痛を生じる損傷の例には、ペーパーカット、軽い熱傷(第1度)、および裂傷が含まれる。
体性痛は、靱帯、腱、骨、血管および神経そのものさえもが起源であり、体性痛侵害受容体により感知される。こうした領域における疼痛受容体の希少性ゆえに、皮膚疼痛よりも持続時間の長い、鈍く、局在のはっきりしない疼痛が生じる;例としては足関節ねんざや骨折が挙げられる。
内臓痛は、身体器官および内部空洞内に位置する身体器官の内臓侵害受容器が起源である。こうした領域において侵害受容器はさらに希少であることから、体性痛よりも疼(うず)きかつ持続時間の長い疼痛が生じる。内臓痛は場所を特定するのが極めて困難であり、内臓組織への複数の損傷は「遠隔痛」という、損傷の部位と全く関連しない領域に前記感覚が限定される痛みを示す。心筋虚血(心筋組織の一部への血流の喪失)は、おそらく遠隔痛の最もよく知られた例である;前記感覚は胸郭上部に束縛された感覚として、または左肩、腕または時には手に、疼きとして生じうる。
幻肢痛とは、もはやないまたはもはやそこから物理的シグナルの来ない肢からの疼痛感覚であり、これは肢切断者および四肢麻痺者がほぼ例外なく訴える体験である。神経因性疼痛(「神経痛」)は、神経組織そのものの損傷または疾患の結果生じうる。これは、感覚神経が視床に正しい情報を伝達する機能を妨害する可能性があり、それ故に脳は明らかなまたは確認された生理学的疼痛原因がないにも関わらず疼痛性刺激を読み取る。
GPR86は、Gタンパク質共役型受容体ファミリーの他のタンパク質と構造的に関連しており、このことはヒトGPR86をコードする増幅されたcDNA産物を配列決定した結果に示された通りである。配列番号1のcDNA配列はオープンリーディングフレーム(配列番号2、ヌクレオチド番号19〜1084)を含み、これは配列番号3に示す354アミノ酸のポリペプチドをコードする。ヒトGPR86がホモ・サピエンス染色体3q24にマッピングされることを見出した。配列番号6の別のcDNAは、配列番号7に記載のポリペプチドをコードする。
KIAA0001推定Gタンパク質共役型受容体;UDP-グルコースに対するGタンパク質共役型受容体;同一性 = 140/295 (47%)、陽性 = 193/295 (64%)
血小板活性化受容体ホモログ[ホモ・サピエンス];同一性 = 42/144 (29%)、陽性 = 78/144 (54%)。
本明細書において用いる、「GPR86ポリペプチド」という用語は、配列番号3もしくは配列番号5もしくは配列番号7に記載のアミノ酸配列を含むポリペプチド、またはそのホモログ、変異体もしくは誘導体を言うことを意図したものである。好ましくは該ポリペプチドは、配列番号3もしくは配列番号7に記載の配列を含むかまたはそのホモログ、変異体または誘導体である。最も好ましくは、該ポリペプチドは、配列番号7に示す配列を含むかまたはそのホモログ、変異体または誘導体である。
本発明者らは、GPR86ポリヌクレオチド、GPR86ヌクレオチドおよびGPR86核酸、これらの製造方法、使用方法などを、本明細書中でさらに別途詳述する。
本明細書に記載のあらゆる配列に関して配列同一性は、1以上の配列と別の配列との単純な「視認(eyeball)」比較(すなわち厳しい比較)によって決定することができ、これによりその別の配列が例えば本配列と少なくとも70%配列同一性を有するかを調べることができる。
本発明者らは、本明細書に記載の配列、またはその任意の断片もしくは誘導体、または前記のいずれかのものの相補配列にハイブリダイズすることのできるヌクレオチド配列をさらに記載する。
本発明者らは、本明細書に記載の配列またはその任意の断片もしくは誘導体に相補的なヌクレオチド配列を記載する。前記配列がその断片に相補的であれば、その配列は他の生物などで類似のGPCR配列を同定およびクローニングするためにプローブとして使用することができる。
クローニングされた推定GPR86ポリヌクレオチドは、配列分析または機能性アッセイにより確認することができる。例えば、推定GPR86またはホモログは次のように受容体活性をアッセイすることができる。GPR86受容体cDNAをコードする線状化プラスミド鋳型由来のキャップ構造を付加されたRNA転写産物は、標準法に沿ってin vitroでRNAポリメラーゼを用いて合成される。In vitro転写産物は水に最終濃度0.2 mg/mlで懸濁される。成体メスヒキガエルから卵巣の葉を移し、第Vステージの濾胞除去卵母細胞を得て、RNA転写産物(10 ng/卵母細胞)をマイクロインジェクション装置を用いて50 nlボーラスとして注入する。2つの電極電圧留め具を使用して、アゴニスト曝露に応答する個々のゼノパス(Xenopus)卵母細胞からの電流を測定した。記録は、(mM表示で) NaCl 115、KCl 2.5、CaCl2 1.8、NaOH-HEPES 10、 pH7.2からなる標準媒体中で室温で行った。ゼノパス(Xenopus)系はまた、活性化リガンドを求めて既知のリガンドと組織/細胞抽出物をスクリーニングするために使用可能であり、これは下に詳述する通りである。
GPR86関連障害を治療するための有用な治療薬を設計するためには、(野生型であれ特定の変異型であれ)GPR86の発現プロファイルを決定することが役に立つ。このことから、当技術分野で既知の方法を、GPR86が発現される器官、組織および細胞型(ならびに発達段階)を決定するのに使用することができる。例えば、伝統的または「電子的」ノーザン分析を行うことができる。逆転写酵素PCR(RT-PCR)もまた、GPR86遺伝子または変異体の発現をアッセイするのに利用可能である。GPR86の発現プロファイルを決定するためのより高感度な方法としては、当技術分野で既知のRNAseプロテクションアッセイが挙げられる。
本発明にはさらにGPR86ポリペプチドの製造方法も含まれる。この方法は一般にGPR86ポリペプチドをコードする核酸またはそのホモログ、変異体もしくは誘導体を含む宿主細胞を、適当な条件下で(すなわちGPR86ポリペプチドが発現される条件で)培養することを含む。
GPR86ポリペプチド、核酸、プローブ、抗体、発現ベクターおよびリガンドはバイオセンサーとして(およびその製造のために)有用である。
GPR86ポリペプチド(ホモログ、変異体、および誘導体も含まれる)は、天然であれ組換えであれ、受容体に結合する化合物、またはGPR86を活性化する(アゴニスト)もしくは活性化を阻害する(アンタゴニスト)化合物をスクリーニングする方法に用いることができる。
本発明者らはさらに、天然または組換えGPR86、またはそのホモログ、変異体もしくは誘導体を、正常な発現レベルと比較して正常レベル、増加されたレベルまたは低減されたレベルで発現することのできるトランスジェニック動物を開示する。好ましくはこうしたトランスジェニック動物は非ヒト哺乳動物、例えばブタ、ヒツジまたは齧歯類である。最も好ましくはトランスジェニック動物はマウスまたはラットである。
本発明の目的において「抗体」という用語には、特に断らない限り、限定するものではないが、ポリクローナル抗体、モノクローナル抗体、キメラ抗体、一本鎖抗体、Fabフラグメント、およびFab発現ライブラリーにより産生されるフラグメントが含まれる。こうしたフラグメントには、標的物質に対する結合活性を保持する全抗体のフラグメント、Fv、F(ab')、およびF(ab')2フラグメント、ならびに、一本鎖抗体(scFv)、融合タンパク質および抗体の抗原結合部位を含有する他の合成タンパク質が含まれる。抗体およびそのフラグメントはヒト化抗体(例えばEP-A-239400に記載のもの)であってもよい。さらに、
完全にヒトの可変領域(またはそのフラグメント)をもつ抗体(例えば米国特許第5,545,807号および第6,075,181号に記載のもの)も使用することができる。中和抗体、すなわち、物質アミノ酸配列の生物学的活性を阻害する抗体は、診断および治療に特に好ましい。
本発明者らはさらに、診断試薬として診断にまたは遺伝分析に使用するための、GPR86ポリヌクレオチドおよびポリペプチド(ならびにそれらのホモログ、変異体および誘導体)の使用を記載する。GPR86核酸(ホモログ、変異体および誘導体を含む)と相補的なまたはハイブリダイズすることができる核酸、ならびにGPR86ポリペプチドに対する抗体もこうしたアッセイに有用である。
GPR86ヌクレオチド配列はまた、染色体同定にも有用である。該配列は、特定のヒト染色体上の特定の位置に特異的に標的化されておりかつそれとハイブリダイズすることができる。上述の様にヒトGPR86はホモ・サピエンス染色体3q24にマッピングされていることが見出されている。
本発明者らは、GPR86活性の過剰と不足の両方に関係する異常状態を治療する方法を提供する。
ペプチド(例えば、可溶性形態のGPR86ポリペプチド、アゴニストおよびアンタゴニストペプチド)または小分子は、好適な製薬上の担体と組み合わせて製剤化することができる。かかる製剤は、治療上有効な量のポリペプチドまたは化合物および製薬上許容される担体または賦形剤を含んでなる。かかる担体には、限定するものでないが、生理食塩水、緩衝化生理食塩水、ブドウ糖、水、グリセロール、エタノール、およびそれらの組み合わせが含まれる。製剤は投与様式に適合すべきであり、これは当業者に周知である。本明細書はまた、さらに、上記の組成物の1以上の成分を充填した1以上の容器を含んでなる医薬用パックおよびキットに関する。
本発明者らはまた、投与するための治療上有効な量のGPR86ポリペプチド、ポリヌクレオチド、ペプチドベクターまたは抗体(本明細書に記載)、および、場合により、製薬上許容される担体、希釈剤もしくは賦形剤(それらの組み合わせを含む)を含んでなる医薬組成物を提供する。
別の実施形態は、哺乳動物における免疫応答を誘発させる方法であって、該哺乳動物に、抗体を産生させかつ/またはT細胞免疫応答を生じて前記動物をGPR86関連疾患から保護するのに十分なGPR86ポリペプチドまたはその断片を接種することを含む前記方法に関する。
典型的には、医師は、個々の被験者に最も適切な実投与量を決定するが、これはその特定の患者の年齢、体重および応答によって変化しうる。以下の投与量は、平均的な事例の例示である。勿論、より高いまたはより低い投与量範囲が有利である場合もありうる。
本発明のさらなる態様および実施形態を以下に番号付けした段落に記載する;本発明はこれらの態様を包含すると理解されたい。
GPR86遺伝子を含有するPACを、そのコード配列の一部から誘導した放射能標識プローブを用いてPACライブラリーから同定した。8.0kbのゲノムコンティグを、GeneWalker (Clontech)に類似するインハウス(in-house)の制限部位アンカーPCR法を用いてアセンブルした。さらなる生物情報工学的(bio-informatic)研究から、コンティグサイズを300kbまで広げた。このコンティグは、ターゲティングベクターへとクローニングする相同アームの設計を可能にするのに十分なフランキング配列情報を提供した。
C57BL/6メスおよび雄マウスを交配させ、妊娠から3.5日に胚盤胞を単離した。胚盤胞1個当たりに選択したクローンからの10〜12個の細胞を注入し、7〜8個の胚盤胞を偽妊娠F1メスの子宮に移植した。高レベル(最高100%)の縞模様(agouti)をもつ複数の雄(縞模様の毛の色が標的クローンの子孫である細胞の寄与を示す)を含むキメラな子の同腹仔が産まれた。この雄キメラを雌MF1および129マウスと交配させ、生殖細胞系列の伝達を、それぞれ縞模様の毛の色およびPCR遺伝子型判定により確認した。
RT-PCRを用いて、肝臓および白血球における該遺伝子の発現を示した(図3)。
ヒトおよびマウスの両方からのcDNAライブラリーを使用するRT-PCRを用いてGPR86 mRNAの発現を調べた。ヒト配列については、プライマー:
フォワード 5’-GGTGTTTGTTCACATCCCCAGC-3’
リバース 5’-TGGTGTTGCTTCCTTGTTGCTC-3’
を用いて364bpの産物を得ることができる。
85℃ ホットスタート
94℃ 15秒
60℃ 30秒を40サイクル
72℃ 60秒
4℃ ホールド
テールフリック無痛覚測定機を用いてテールフリック無痛覚テストを行った。この装置は齧歯類の疼痛感受性を正確にかつ再現性をもって決定する簡便な方法を提供する(D’Amour, F.E. and D.L. Smith, 1941, Expt. Clin. Pharmacol., 16: 179-184)。この器具にはシャッター制御ランプが熱源として付いている。ランプは動物の下に配置され、さほど監禁的ではない環境を提供する。尾を掉る行動(テールフリック)は自動感知回路により感知され、これにより使用者は手で自由に動物を扱うことができる。動物を換気されるチューブに拘束し、その尾を装置の上の感知溝の上に配置する。
ホルマリンテストは、後足に注入された有毒物質への応答を測定する。20μlの容量の5%ホルマリン溶液を、細い標準規格注射針を用いて一つの後足の背面に皮下注射する。後足を舐める、振る、および咬む行動を、その行動にかけた累積秒数として定量する。次の評価尺度を用いる:1=ホルマリン注射した足を床に軽く横たわらせ体重をあまりかけない;2=注射した足を持ち上げる;3=注射した足を舐める、咬むまたは振る。
疼痛閾値を測定するために使用される、触覚のテストはvon Frey hairを用いる。このヘアは非常に細いゲージ目盛り付きワイヤーのセットである。機械的刺激に対する離脱閾値を測定する。動物を、表面が寸法の広いワイヤーメッシュである持ち上がった台の上に立たせる。Von Freyヘアを下から、メッシュの穴の間から挿入し、後足の下部表面を突く。閾値で、マウスは足をヘアから離すようにふる反応を示し、一般にその次に足を上げる、足を舐めるおよび/または声を出す。機械的離脱閾値は、3回の連続施行中2回の離脱反応を引き起こす最小ゲージワイヤー刺激と定義される。
神経因性疼痛は、麻酔マウスのL5脊髄神経をきつく結紮することにより誘発させることができる(Kim and Chung 1992)。回復後、神経因性疼痛の発達と維持を、異痛(非有害刺激に対する疼痛の知覚)および痛覚過敏(有害刺激に対する応答増加)について測定することができる。
Claims (28)
- GPR86関連疾患、特に炎症性疾患または疼痛の治療、予防または緩和に好適な分子の同定方法であって、候補分子がGPR86ポリペプチドのアゴニストまたはアンタゴニストであるか否かを判別することを含み、ただし前記GPR86ポリペプチドは配列番号3もしくは配列番号5もしくは配列番号7に記載のアミノ酸配列、その断片またはそれに少なくとも90%同一な配列を含む、前記方法。
- 前記GPR86ポリペプチドが、配列番号1、配列番号2もしくは配列番号4に記載の核酸配列、またはそれに少なくとも90%同一な配列によりコードされる、請求項1に記載の方法。
- 前記候補分子をGPR86ポリペプチドに曝露すること、および該候補分子がGPR86ポリペプチドに結合するか否かを判別することを含む、請求項1または2に記載の方法。
- GPR86優先的Gタンパク質Giと共役しているGPR86受容体を含む細胞を候補化合物と接触させること、および、該細胞中のサイクリックAMP(cAMP)のようなGPCR感受性マーカーのレベルが前記接触の結果低下するか否かを測定すること、によりアゴニストを同定する、請求項1、2または3に記載の方法。
- GPR86優先的Gタンパク質Giと共役しているGPR86受容体を含む細胞を候補化合物と接触させること、および、該細胞中のサイクリックAMP(cAMP)のようなGPCR感受性マーカーのレベルが前記接触の結果増加するか否かを測定すること、によりアンタゴニストを同定する、請求項1、2または3に記載の方法。
- Gα16のような無差別刺激性Gタンパク質と共役しているGPR86受容体を含む細胞を候補化合物と接触させること、および、該細胞中のサイクリックAMP(cAMP)のようなGPCR感受性マーカーのレベルが前記接触の結果増加するか否かを測定すること、によりアゴニストを同定する、請求項1、2または3に記載の方法。
- Gα16のような無差別刺激性Gタンパク質と共役しているGPR86受容体を含む細胞を候補化合物と接触させること、および、該細胞中のサイクリックAMP(cAMP)のようなGPCR感受性マーカーのレベルが前記接触の結果低下するか否かを測定すること、によりアンタゴニストを同定する、請求項1、2または3に記載の方法。
- (a) 野生型動物または機能破壊された内因性GPR86遺伝子を有するトランスジェニック非ヒト動物を用意すること;
(b) 前記野生型動物またはトランスジェニック非ヒト動物を候補分子に曝露すること;および
(c) 前記動物の生物学的パラメーターが前記接触の結果変化したか否かを測定することを含む、請求項1または2に記載の方法。 - 前記生物学的パラメーターが、刺激への応答、熱への応答、光への応答、免疫応答、炎症反応、疼痛への応答、好ましくは疼痛への応答からなる群より選択される、請求項8に記載の方法。
- (a) 野生型細胞または機能破壊された内因性GPR86遺伝子を含む細胞、好ましくは機能破壊された内因性GPR86遺伝子を有するトランスジェニック非ヒト動物から単離された細胞を用意すること;
(b) 前記細胞を候補分子に曝露すること;および
(c) GPR86ポリペプチドの生物学的活性が前記接触の結果変化したか否かを測定することを含む、請求項1または2に記載の方法。 - GPR86関連疾患、特に炎症性疾患または疼痛の治療、予防または緩和に用いるためのGPR86ポリペプチドのアゴニストまたはアンタゴニストの同定方法における、野生型動物または機能破壊された内因性GPR86遺伝子を有するトランスジェニック非ヒト動物の使用。
- 機能破壊された内因性GPR86遺伝子を有するトランスジェニック非ヒト動物またはその単離された細胞もしくは組織の、GPR86関連疾患、特に炎症性疾患または疼痛のモデルとしての使用。
- 前記トランスジェニック非ヒト動物が、機能破壊されたGPR86遺伝子、好ましくはGPR86遺伝子もしくはその一部分に欠失を有する機能破壊されたGPR86遺伝子を含む、請求項8〜12のいずれか1項に記載の使用または方法。
- 前記トランスジェニック非ヒト動物が、野生型動物と比較した場合に次の表現型のいずれか1つ以上:刺激への応答、熱への応答、光への応答、免疫応答、炎症反応、疼痛への応答、好ましくは疼痛への応答、に変化を示す、請求項8〜13のいずれか1項に記載の使用または方法。
- 前記トランスジェニック非ヒト動物が、少なくとも次の1つ:野生型動物と比較した場合の、(a)増加または減少した疼痛感受性である変更された疼痛感受性、および(b)増加または減少した炎症性疼痛感受性である変更された炎症性疼痛感受性、を示す、請求項8〜14のいずれか1項に記載の使用または方法。
- 前記トランスジェニック非ヒト動物が、齧歯類、好ましくはマウスである、請求項8〜15のいずれか1項に記載の使用または方法。
- GPR86ポリペプチドのアゴニストまたはアンタゴニストの同定方法であって、候補化合物を請求項4〜16のいずれか1項に記載の野生型またはトランスジェニック非ヒト動物に投与すること、および請求項9に記載の生物学的パラメーターの変化を測定することを含む、前記方法。
- GPR86関連疾患、特に炎症性疾患または疼痛の治療、予防のためのGPR86のアゴニストまたはアンタゴニストを同定するための、配列番号3もしくは配列番号5もしくは配列番号7に記載のアミノ酸配列、その断片またはそれに少なくとも90%同一な配列を含むGPR86ポリペプチドの使用。
- GPR86関連疾患、特に炎症性疾患または疼痛の治療、予防のためのGPR86のアゴニストまたはアンタゴニストを同定するための、配列番号1、配列番号2もしくは配列番号4に記載の核酸配列、もしくはその断片、またはそれに少なくとも90%同一な配列を含むGPR86ポリヌクレオチドの使用。
- 疼痛が、急性疼痛、慢性疼痛、皮膚疼痛、体性痛、内臓痛、心筋虚血、幻肢痛(phantom pain)、および神経因性疼痛(神経痛)を含む遠隔痛、損傷、疾患に起因する疼痛、頭痛、偏頭痛、癌疼痛、パーキンソン病のような神経障害に起因する疼痛、脊椎および末梢神経手術、脳腫瘍、外傷性脳損傷(TBI)、脊髄外傷、慢性疼痛症候群、慢性疲労症候群に起因する疼痛、三叉神経痛、舌咽神経痛、ヘルペス後神経痛、およびカウザルギーなどの神経痛、狼瘡、サルコイドーシス、くも膜炎、関節炎、リウマチ性疾患、生理痛、背痛、腰痛、関節痛、腹痛、胸痛、陣痛、骨格筋疾患および皮膚病、頭部外傷、ならびに線維筋痛のいずれかにより生じる疼痛からなる群より選択される、請求項1〜19のいずれか1項に記載の方法。
- 炎症性疾患が炎症性障害から選択され、好ましくは炎症性疾患(例えば慢性関節リウマチ、多発性硬化症、ギラン・バレー症候群、クローン病、潰瘍性大腸炎、乾癬、移植片対宿主拒絶反応、全身性エリテマトーデスまたはインスリン依存性糖尿病)、自己免疫疾患(例えば毒素性ショック症候群、変形性関節症、糖尿病または炎症性腸疾患)、急性疼痛、慢性疼痛、神経因性疼痛、接触皮膚炎、アテローム動脈硬化症、糸球体腎炎、再灌流障害、骨吸収障害、喘息、卒中、心筋梗塞、熱傷、成人呼吸窮迫症候群(ARDS)、外傷に続発する多器官障害、急性炎症性成分を伴う皮膚病、急性化膿性髄膜炎、壊死性腸炎、血液透析に付随する症候群、敗血症ショック、白血球搬出法、顆粒球輸血、煙吸入により引き起こされる肺の急性または慢性炎症、子宮内膜症、ベーチェット病、ブドウ膜炎、強直性脊椎炎、膵炎、癌、ライム病、経皮経管冠状動脈形成に続く再狭窄、アルツハイマー病、外傷性関節炎、敗血症、慢性閉塞性肺疾患、うっ血性心不全、骨粗鬆症、悪液質、パーキンソン病、歯周病、痛風、アレルギー疾患、加齢性黄班変性症、感染および膿胞性線維症から成る群より選択される、請求項1〜20のいずれか1項に記載の方法。
- 請求項1〜21のいずれか1項に記載の方法または使用により同定されたGPR86のアゴニストまたはアンタゴニスト。
- GPR86関連疾患、特に炎症性疾患または疼痛の治療、予防または緩和のための、請求項22に記載の分子の使用。
- GPR86関連疾患、特に炎症性疾患もしくは疼痛またはそれに対する易罹患性を診断するキットであって、次のいずれか1以上:GPR86ポリペプチドまたはその一部分;GPR86ポリペプチドに対する抗体;またはこうしたものをコードしうる核酸、を含む前記キット。
- GPR86関連疾患、特に炎症性疾患もしくは疼痛を患っている個体の治療方法であって、前記個体におけるGPR86ポリペプチドの活性または量を増加または減少させることを含む前記方法。
- GPR86ポリペプチド、GPR86ポリペプチドのアゴニストまたはGPR86のアンタゴニストを前記個体に投与することを含む、請求項25に記載の方法。
- GPR86関連疾患、特に炎症性疾患もしくは疼痛の診断方法であって、次のステップ:
(a) こうした疾患に罹患しているかまたは罹患している疑いのある動物におけるGPR86ポリペプチドの発現レベルまたは発現パターンを検出すること;および
(b) 該発現レベルまたは発現パターンを正常動物のそれと比較すること、
を含む前記方法。 - 図1〜7を参照しそれらに示されている、本明細書に実質的に記載された方法または使用。
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WO2001027153A1 (en) * | 1999-10-13 | 2001-04-19 | Smithkline Beecham Corporation | A murine seven-transmembrane receptor, mus musculus mhneaa81 |
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