JP2006513723A - Gpr54ノックアウト哺乳動物とそれを用いるスクリーニング方法 - Google Patents
Gpr54ノックアウト哺乳動物とそれを用いるスクリーニング方法 Download PDFInfo
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Abstract
Description
ヒト組織において、ノーザン分析は脳/神経系(皮質、被殻、髄質、脊髄における発現および海馬、視床における低発現)ならびに下垂体、心臓、骨格筋、腎臓、肝臓、胃、小腸、胸腺、肺、精巣および胎盤における発現を示す(Clementsら, 2001 Biochem Biophys Res Commun 284:1189-93;Kotaniら, 2001 J Biol Chem 276:34631-36)。
本発明者らは、GPR54のin vivoでの役割を研究する目的で、GPR54(Harry Potter)ノックアウトマウスを作製した。本発明者らは、かかるノックアウトマウスが非突然変異体とは生殖形態学および生理学に相違のあることを示し、性ホルモン軸の制御における、また、受胎能および性欲の制御などの生殖領域におけるGPR54の役割を提起した。さらに、かかる突然変異体の生理学および形態学は、ある特定の神経学的障害および他の症状(例えば、筋消耗および炎症)におけるGPR54の役割を示唆する。
(a)1以上の機能的に活性のある内因性GPR54遺伝子を含有する1以上の細胞を選択するステップ、
(b)ステップ(a)で選択した1以上の細胞に、相同的組換えにより1以上の内因性GPR54遺伝子と組換えることができる機能的に不活性なGPR54核酸をトランスフェクトするステップ、および
(c)1以上の内因性GPR54遺伝子が機能的に不活性なGPR54核酸による相同的組換えを受けた1以上の細胞を選択するステップ、
を含んでなる上記方法を提供する。
(a)非相同置換領域、
(b)非相同置換領域の上流に位置する第1相同領域、
(c)発現した時に機能的に活性なGPR54をコードしない突然変異型GPR54遺伝子、
(d)非相同置換部分の下流に位置する第2相同領域であって、非相同置換領域の下流に位置し、第2のGPR54遺伝子に対して少なくとも90%の同一性を示すヌクレオチド配列を有する第2相同領域、
を含んでなる上記核酸構築物を提供する。
(a)ゴナドトロピンが低いこと;
(b)少なくとも卵巣は外因性ゴナドトロピンの投与に応答し、これは卵巣が応答能力を保持することを示すこと;および
(c)GnRHの外因性投与はFSHとLHの分泌の少なくとも部分的応答を惹起し、これはGPR54が視床下部-下垂体におけるGnRH分泌の上流制御に関わりうることを示すこと。
(a)機能的に不活性なGPR54ポリペプチドを含有する1以上の哺乳動物を選択するステップ、
(b)これらの1以上の哺乳動物を、GPR54活性の少なくとも1つを潜在的に作動させる1以上の潜在的GPR54擬似体により処置するステップ、
(c)ステップ(b)で処置したこれらの1以上の哺乳動物を試験して、これらの処置した哺乳動物が、ステップ(a)で選択した哺乳動物と比較して1以上の回復した特徴を有するか否かを確認するステップ、および
(d)ステップ(a)で選択したこれらの哺乳動物に、野生型哺乳動物の1以上の特徴を回復させる1以上のGPR54リガンド擬似体を選択するステップ、
を含んでなる上記方法を提供する。
(a)機能的に活性なGPR54ポリペプチドを含有する1以上の哺乳動物を選択するステップ、
(b)これらの1以上の哺乳動物を、GPR54活性の少なくとも1つに潜在的に拮抗する1以上の潜在的GPR54アンタゴニストにより処置するステップ、および
(c)ステップ(b)で処置したこれらの1以上の哺乳動物を試験して、これらの処置した哺乳動物が、ステップ(a)で選択した哺乳動物と比較して1以上のモジュレートされた特徴を有するか否かを確認するステップ、
を含んでなる上記方法を提供する。
(a)診断すべき患者から細胞サンプルを選択するステップ、ならびに
(b)これらの細胞サンプル中のGPR54ポリペプチドの発現レベルおよび/または機能的活性を、健康な個体からの1以上の対照サンプルと比較するステップ、
を含んでなる上記方法を提供する。
(a)診断すべき患者から細胞サンプルを選択するステップ、ならびに
(b)上記細胞中の内因性核酸を分析して、内因性GPR54遺伝子またはGPR54の1以上の天然リガンドの1以上の多形を検出するステップ、
を含んでなる上記方法を提供する。
一般技術
本発明の実施は、特に断らない限り、化学、分子生物学、微生物学、組換えDNAおよび免疫学の通常の技術を利用しうるのであって、これらは当業者の能力の範囲内にある。かかる技術は文献に記載されている。例えば、J. Sambrook, E.F. FritschおよびT. Maniatis, 1989, 「分子生物学:実験室マニュアル(Molecular Cloning: A Laboratory Manual)」, 第2版, 1-3分冊, Cold Spring Harbor Laboratory Press;Ausubel, F.M.ら, 1995および定期的追補版, 「分子生物学の現代プロトコル(Current Protocols in Molecular Biology)」, 第9、13および16章, John Wiley & Sons, New York, N.Y.;B. Roe, J. CrabtreeおよびA. Kahn, 1996, 「DNA単離と配列決定:必須技術(DNA Isolation and Sequencing: Essential Techniques)」, John Wiley & Sons;J.M. PolakおよびJames O'D. McGee, 1990, 「in situハイブリダイゼーション:原理と実施(In Situ Hybridization: Principles and Practice)」, Oxford University Press;M.J. Gait (編), 1984, 「オリゴヌクレオチド合成:実用的手法(Oligonucleotide Synthesis: A Practical Approach)」, Irl Press;ならびに、D.M.J. LilleyおよびJ.E. Dahlberg, 1992, 「酵素学の方法:DNA構造パートA:DNAの合成と物理分析(Methods of Enzymology: DNA Structure Part A: Synthesis and Physical Analysis of DNA)」, Methods in Enzymology, Academic Pressを参照されたい。これらの一般的教科書は本明細書に参照により組み入れられる。
疑義を避けるために、本明細書において用語「GPR54」は、関係するGenBank登録番号により同定される次の配列を意味するものとする:
NT_011255 ホモサピエンス(Homo sapiens)第19染色体ゲノムコンティグ;NM_053244 マウス(Mus musculus)Gタンパク質共役受容体54(Gpr54)、mRNA;BC016531 マウス(Mus musculus)Gタンパク質共役受容体54、mRNA(cDNAクローンMGC:27839 IMAGE:3488082)、完全cds;M_032551 ホモサピエンス(Homo sapiens)Gタンパク質共役受容体54(GPR54)、mRNA;NM_023992 ドブネズミ(Rattus norvegicus)Gタンパク質共役受容体54(Gpr54)、mRNA;NW_047773 ドブネズミ(Rattus norvegicus)第7染色体 WGSスーパーコンティグ;AK039628 マウス(Mus musculus)成熟雄脊髄cDNA、RIKEN 全長富化ライブラリー、クローン:A330075J02 産物:Gタンパク質共役受容体GPR54(Gタンパク質共役受容体54)、全インサート配列;NT_039496 マウス(Mus musculus)第10染色体ゲノムコンティグ、株C57BL/6J;AY029541 ホモサピエンス(Homo sapiens)推定Gタンパク質共役受容体mRNA、完全cds;AF343726 マウス(Mus musculus)Gタンパク質共役受容体GPR54(Gpr54)mRNA、完全cds;AF343725 ホモサピエンス(Homo sapiens)Gタンパク質共役受容体GPR54(GPR54)mRNA、完全cds;BE506644 db65f08.y1 Wellcome CRC pSK卵子アフリカツメガエル(Xenopus laevis)cDNAクローンIMAGE:3377895 5'、TR:Q9Z0T7 Q9Z0T7オーファンGタンパク質共役受容体GPR54と類似、mRNA配列;BB261471 BB261471 RIKEN全長富化、7日新生仔小脳マウス(Mus musculus)cDNAクローンA730098N23 3'、AF115516 ドブネズミ(Rattus norvegicus)オーファンGタンパク質共役受容体GPR54(GPR54)mRNAと類似、mRNA配列;AF115516 ドブネズミ(Rattus norvegicus)オーファンGタンパク質共役受容体GPR54(GPR54)mRNA、完全cds。
本明細書に記載の用語「ポリペプチド」は、ペプチド結合または修飾されたペプチド結合、すなわちペプチドイソスター(peptide isostere)によって互いに結合された2個以上のアミノ酸を含む任意のペプチドまたはタンパク質を意味する。「ポリペプチド」は、通常、ペプチド、オリゴペプチドまたはオリゴマーと呼ばれる短鎖、および通常、タンパク質と呼ばれる長鎖の両方を意味する。ポリペプチドは、遺伝子によりコードされる20種のアミノ酸以外のアミノ酸を含んでもよい。
「ポリヌクレオチド」は、一般的に、任意のポリリボヌクレオチドまたはポリデオキシリボヌクレオチドを意味し、非改変のRNAもしくはDNAまたは改変したRNAもしくはDNAのいずれであってもよい。「ポリヌクレオチド」は、限定されるものでないが、一本鎖および二本鎖DNA、一本鎖と二本鎖領域の混合物であるDNA、一本鎖および二本鎖RNA、一本鎖および二本鎖領域の混合物であるRNA、一本鎖、より典型的には、二本鎖または一本鎖と二本鎖領域の混合物であってもよいDNAおよびRNAを含んでなるハイブリッド分子を含む。さらに、「ポリヌクレオチド」は、RNAまたはDNAまたはRNAとDNAの両方を含む三本鎖領域も意味する。用語ポリヌクレオチドはまた、1個以上の修飾された塩基を含有するDNAまたはRNAおよび安定性または他の理由のために修飾された骨格を有するDNAまたはRNAも含む。「修飾された」塩基は、例えば、トリチル化塩基およびイノシンなどの特異な塩基を含む。種々の修飾がDNAおよびRNAに行われている;従って「ポリヌクレオチド」は、自然界で典型的に見出されるポリヌクレオチドの化学的、酵素的、または代謝的に修飾された形態だけでなく、ウイルスおよび細胞に特徴的なDNAおよびRNAの化学的形態も包含する。「ポリヌクレオチド」はまた、しばしばオリゴヌクレオチドと呼ばれる比較的短いポリヌクレオチドも包含する。
GPR54関連疾患の治療に有用な治療薬を設計するためには、GPR54(野生型または特定の変異体のいずれにせよ)の発現プロファイルを確認することが有用である。そこで当技術分野で公知の方法を利用して、GPR54が発現される器官、組織、および細胞型(ならびに発生段階)を確認する。例えば、伝統的または「エレクトロニック」ノーザン分析を行うことができる。逆転写酵素PCR(RT-PCR)を用いて、GPR54遺伝子または突然変異体の発現をアッセイしてもよい。GPR54の発現プロファイルを調べるためのさらに高感度の方法は、当技術分野で公知のRNAアーゼプロテクションアッセイを含む。
GPR54ポリペプチドの発現は、本明細書に記載のGPR54のアゴニストまたはアンタゴニストとして機能しうるGPR54抗体を作製するために必要である。
ノックアウト
本発明のさらなる態様においては、GPR54ポリペプチドを機能的に不活性化した1以上の細胞を含んでなるGPR54ノックアウト哺乳動物を提供する。
(a) GPR54遺伝子ターゲティングベクターの構築
マウスGPR54ゲノムクローンを、HGMP(Hinxton、UK)から得たマウス大インサートPACライブラリーから、推定マウスオープンリーディングフレームcDNA配列(配列番号4)の一部分から増幅したプローブ配列と標準技術を用いて単離する。次いで、単離したマウスGPR54ゲノムクローンを、小さいオリゴヌクレオチドプローブと標準技術を用いて、GPR54遺伝子の領域に制限マッピングする。
胚性幹細胞(EvansおよびKaufman, 1981)を、20%のウシ胎児血清、10%のウシ新生子血清、2mMのグルタミン、非必須アミノ酸類、100μMの2−メルカプトエタノール、および500u/mlの白血病阻害因子を補充したダルベッコ改変イーグル培地中で増殖させたネオマイシン耐性胚性線維芽細胞の支持細胞層上で培養する。培地を毎日交換し、ES細胞を3日毎に継代培養(subculture)する。エレクトロポレーション(25μF静電容量および400ボルト)により5×106個のES細胞に5μgの線状化プラスミドをトランスフェクトする。エレクトロポレーションの24時間後に、トランスフェクトした細胞を、200μg/mlのネオマイシンを含有する培地中で9日間培養する。クローンを96ウェルプレートに拾い、複製させて増やした後、PCRによりスクリーニングして、内因性GPR54遺伝子とターゲティング構築物の間で相同組換えが起こったクローンを同定する。ポジティブクローンは典型的には1〜5%の割合で同定される。これらのクローンを増やしてレプリカを凍結させ、十分に高品質のDNAを調製し、外部5'および3'プローブを用いてターゲティング事象をサザンブロットにより確認するが、これらは全て標準的な手法を用いて行う(Russら, Nature 2000 Mar 2; 404(6773):95-9)。
C57BL/6雌および雄マウスを交配させ、胚盤胞を妊娠3.5日目に単離する。胚盤胞1個あたり選択クローンから得た10〜12個の細胞を注入し、7〜8個の胚盤胞を偽妊娠F1雌の子宮に移植する。
本発明によれば、(好適な対照と比較して)GPR54受容体の過剰発現または該受容体の過小発現をもたらす非ヒトトランスジェニック動物も意図している。
本明細書に記載したように、抗体をGPR54ポリペプチドのアゴニストまたはアンタゴニストとして使用することができる。
さらなる態様においては、本発明は、アルツハイマー病、感覚神経障害および癲癇、受胎能の調節、性欲および思春期の開始、乳汁分泌、骨粗鬆症/大理石骨病、閉経、筋消耗性疾患、疼痛、ホルモン依存性癌および肥満からなる群から選択される疾患または症状を診断する方法であって、
(a)診断する患者から細胞サンプルを選択するステップ、ならびに
(b)これらの細胞サンプル中のGPR54ポリペプチドの発現レベルおよび/または機能的活性を、健康な個体からの1以上の対照サンプルと比較するステップ、
を含んでなる上記方法を提供する。
本発明は、GPR54ポリペプチド活性の過剰と不足の両方に関係する異常な症状を治療する方法を提供するが、GPR54ポリペプチド、その結合タンパク質および/またはそれらをコードする核酸は、神経学的症状、生殖ホルモン関連症状、および特定の他の症状の治療に特に有用であると考えられる。かかる神経学的症状は、限定されるものでないが、アルツハイマー病、感覚神経障害および癲癇のいずれかの1以上を含む。
ペプチド(例えば、可溶性形態のGPR54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。かかる担体は、限定されるものでないが、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を含む。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。本発明は、さらに、本発明の上記の組成物の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。
本発明はまた、治療上有効な量の本発明によるGPR54ポリペプチド、その結合分子またはそれらをコードする核酸、および、場合によっては、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。
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る。
GPR54遺伝子ターゲティングベクターの構築
マウスGPR54遺伝子は生物情報工学的に(bioinformatically)同定し、PACライブラリー由来の10.3kbゲノムコンティグ内に位置することを見出した。さらなる生物情報工学的研究によりこのコンティグを28kbまで広げた。このコンティグは、ターゲティングベクター中にクローニングするための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与えた(利用したターゲティングベクターの、関係する制限酵素切断部位を含む構造を図3に示した)。
C57BL/6雌および雄マウスを交配させ、胚盤胞を妊娠3.5日目に単離する。胚盤胞1個当たり選択クローンから得た10〜12細胞を注入し、7〜8個の胚盤胞を偽妊娠F1雌の子宮に移植した。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)を含むキメラの子の同腹仔が産まれた。これらの雄キメラを雌MF1および129マウスと交配させ、生殖細胞系列の伝達を、縞模様の毛の色およびPCR遺伝子型判定によりそれぞれ確認した。
B)結果
I)遺伝子発現パターン
1)エレクトロニックノーザン
エレクトロニックノーザンを図16に示す。
次の組織は、lacZアッセイにおいてlacZ発現の証拠を含んでいた:脳(以下のサブ領域を参照)、脊髄(感覚領域)、精巣。
6匹の野生型マウスおよび6匹の突然変異GPR54ノックアウトマウスの脳を固定し、凍結ミクロトーム上で40マイクロメーターの切片にカットした。
海馬
嗅球
視交差前の視床下部
室周囲の視床下部
手綱核
視床下部路
蝸牛核
乳頭上体
図4a突然変異体の脳スライスおよび図4bヘテロ接合体および野生型の精巣を参照。
Harry Potterノックアウトマウスは、いくつかの明白な解剖学的異常を表す:突然変異体は、全体的な生殖管の強い萎縮(雄における萎縮包皮腺、小陰茎、極小の精巣および精嚢/凝固腺(coagulatory glands))、減少した筋量、減少した褐色脂肪量、より小さい胃および上顎下唾液腺を有する。
III)行動
全ての動物を、食物と水に自由にアクセスできるようにして明所12時間/暗所12時間の明暗サイクルで午前7時に点灯して飼育した。
a)バーンズ迷路
空間記憶の試験であるバーンズ迷路は、特定場所の識別を要求するように設計した白色円板プラットフォームである。この迷路は、外周沿いに18個の円形孔が均一に配置された円板プラットフォームから成る。そのうちの1個の孔の下に黒い逃走箱が存在する。バーンズ迷路は、げっ歯類が照明の当たる開放された表面を避けて暗所の囲まれた避難所を求める自然性向を利用する。
5匹の雄突然変異体および5匹の野生型同腹仔を、発情期の野生型雌(膣スメアにより評価)とともに新しいケージに入れて30分間観察した。両方とも雌に関心を示し(嗅ぐ動作をして)、観察時間内に交配した。
6匹の突然変異体雌と6匹の野生型同腹仔を5連続日の間、スメア試験に供した。4匹の3週齢+/+雌も試験した。スライドをメチレンブルーを用いて染色した。全ての野生型は明白な発情周期の段階を示したが、突然変異体はいずれも示さなかった。-/-雌の膣スメアは3週齢野生型の膣スメアと類似した(図8)。
いずれか一方の性のGPR54突然変異体とその反対の性の野生型マウスとを含む15の交配対を設けたが、いずれも仔を産まなかった。従って、雄および雌のGPR54突然変異体は両方とも生殖不能である。
a)器官重量
精巣(図9)、筋肉(図10)、副腎(図11a)および唾液腺(図11b)の重量を測定した。
a)テストステロン、エストロゲンおよびGnRHアッセイ
6匹の雄突然変異体および6匹の野生型マウスのテストステロンを測定した。突然変異体は、野生型マウスと比較して、著しく低いレベルのテストステロン(P<0.05)を有する(図12)。
突然変異体のFSHは野生型に比べ非常に低い(図14a:雌および図14b:雄)。LHレベルの差はない(データは示してない)。
PMS(妊馬血清−FSH様ゴナドトロピン)1000iuを投与し、続いて2日後にbHCG(βヒト絨毛性ゴナドトロピン)1000iuを投与したところ、突然変異体雌の50%(n=6)に成熟卵母細胞の排卵が起こり、末端器官が天然ゴナドトロピンに応答する能力を保持していることを示した。これは、GPR54受容体とリガンドが下垂体視床下部軸のレベルで作用していて末端器官のレベルで作用していないという仮説と一致する。
方法:GnRHペプチド25ngを4回、30分間隔で注射し、最後の注射の30分後に動物を犠牲にして血液および下垂体を採取した。全てのマウスは11am〜1pmの間に犠牲にした。
Claims (18)
- GPR54ポリペプチドが機能的に不活性化された1以上の細胞を含んでなるGPR54ノックアウト哺乳動物。
- 野生型対照マウスと比較して、接触立ち直り反射の低下およびバーンズ(Barnes)迷路能力の低下、生殖ホルモンのレベルおよび/またはパターン(周期を含む)の変化、生殖器官および関連器官の形態の変化、性/生殖行動の変化からなる群から選択される特徴のいずれか1以上を有する、請求項1に記載のGPR54ノックアウトマウス。
- 生殖ホルモンのレベルおよび/またはパターン(周期を含む)の変化、生殖器官および関連器官の形態の変化、および性/生殖行動の変化からなる群から選択される特徴を有する、請求項2に記載のGPR54ノックアウトマウス。
- 1以上の機能的に不活性なGPR54遺伝子を含む1以上の哺乳動物細胞を作製する方法であって、
(a)1以上の機能的に活性な内因性GPR54遺伝子を含む1以上の細胞を選択するステップ、
(b)ステップ(a)で選択した1以上の細胞に、相同的組換えにより1以上の内因性GPR54遺伝子と組換えることができる機能的に不活性なGPR54核酸をトランスフェクトするステップ、および
(c)1以上の内因性GPR54遺伝子が機能的に不活性なGPR54核酸との相同的組換えを受けた1以上の細胞を選択するステップ、
を含んでなる上記方法。 - 宿主細胞中の1以上の内因性GPR54遺伝子を機能的に不活性化するための核酸構築物であって、
(a)非相同置換領域、
(b)非相同置換領域の上流に位置する第1相同領域、
(c)発現したときに機能的に活性なGPR54をコードしない突然変異型GPR54遺伝子、
(d)非相同置換部分の下流に位置する第2相同領域であって、非相同置換領域の下流に位置し、第2のGPR54遺伝子に対して少なくとも90%の同一性を示すヌクレオチド配列を有する上記第2相同領域、
を含んでなる上記核酸構築物。 - GPR54ポリペプチドもしくはその1以上の結合タンパク質またはそれらをコードする核酸、および製薬上許容される担体、希釈剤または賦形剤を含んでなる組成物。
- GPR54ポリペプチドの機能的活性の1以上のアンタゴニストを同定する方法であって、
(a)機能的に活性なGPR54ポリペプチドを含有する1以上の哺乳動物を選択するステップ、
(b)これらの1以上の哺乳動物をGPR54ポリペプチドの1以上の潜在的アンタゴニストにより処置するステップ、
(c)これらの1以上の哺乳動物を試験して、これらの哺乳動物がGPR54ノックアウトマウスにより示される異常な神経学的特徴ならびに異常な生殖系および/または形態からなる群から選択される1以上の特徴を示すか否かを確認するステップ、
(d)ステップ(c)で確認した特徴の1以上を示す1以上のアンタゴニストを選択するステップ、
を含んでなる上記方法。 - ステップ(c)が、これらの1以上の哺乳動物を試験して、これらの哺乳動物が生殖系および/または形態の異常を示すか否かを確認することを含む、請求項7に記載の方法。
- GPR54ポリペプチドの機能的活性を作動させる1以上の分子を同定する方法であって、
(a)機能的に不活性なGPR54ポリペプチドを含有する1以上の哺乳動物を選択するステップ、
(b)これらの1以上の哺乳動物を、GPR54活性の少なくとも1つを潜在的に作動させる1以上の潜在的GPR54擬似体により処置するステップ、
(c)ステップ(b)で処置したこれらの1以上の哺乳動物を試験して、これらの処置した哺乳動物が、ステップ(a)で選択した哺乳動物と比較して1以上の回復した特徴を有するか否かを確認するステップ、および
(d)ステップ(a)で選択したこれらの哺乳動物に、野生型哺乳動物の1以上の特徴を回復させる1以上のGPR54リガンド擬似体を選択するステップ、
を含んでなる上記方法。 - GPR54ポリペプチドの機能的活性に拮抗する1以上の分子を同定する方法であって、
(a)機能的に活性なGPR54ポリペプチドを含有する1以上の哺乳動物を選択するステップ、
(b)これらの1以上の哺乳動物を、GPR54活性の少なくとも1つに潜在的に拮抗する1以上の潜在的GPR54アンタゴニストにより処置するステップ、および
(c)ステップ(b)で処置したこれらの1以上の哺乳動物を試験して、これらの処置した哺乳動物が、ステップ(a)で選択した哺乳動物と比較して1以上のモジュレートされた特徴を有するか否かを確認するステップ、
を含んでなる上記方法。 - 1以上の化合物の生物学的効果についてのアッセイにおける、トランスジェニックGPR54ノックアウト哺乳動物の使用。
- アルツハイマー病、感覚神経障害および癲癇、受胎能の調節、性欲および思春期の開始、乳汁分泌、骨粗鬆症/大理石骨病、閉経、筋消耗性疾患、疼痛、ホルモン依存性癌ならびに肥満からなる群から選択される疾患または症状を診断する方法であって、
(a)診断すべき患者から細胞サンプルを選択するステップ、
(b)これらの細胞サンプル中のGPR54ポリペプチドの発現レベルおよび/または機能的活性を健常な個体からの1以上の対照サンプルと比較するステップ、
を含んでなる上記方法。 - アルツハイマー病、感覚神経障害および癲癇、受胎能の調節、性欲および思春期の開始、乳汁分泌、骨粗鬆症/大理石骨病、閉経、筋消耗性疾患、疼痛、ホルモン依存性癌ならびに肥満からなる群から選択される疾患または症状を診断する方法であって、
(a)診断すべき患者から細胞サンプルを選択するステップ、
(b)これらの細胞からの核酸を試験し、GPR54遺伝子の1以上の多形を検出するステップ、
を含んでなる上記方法。 - 少なくともある割合の細胞中に、GPR54ポリペプチド、GPR54ポリペプチドの1以上のアゴニスト、GPR54ポリペプチドの1以上のアンタゴニスト、およびGPR54活性の1以上のモジュレーターからなる群から選択される1以上をコードする外因性核酸を含有する、トランスジェニック動物。
- 筋消耗性疾患、疼痛、炎症、ホルモン依存性癌、乳汁分泌、骨粗鬆症/大理石骨病、閉経に関係するホルモン不均衡、ならびに肥満からなる群から選択される患者の症状を治療する方法であって、治療上有効な量のGPR54ポリペプチド、GPR54ポリペプチドの1以上のアゴニスト、GPR54ポリペプチドの1以上のアンタゴニスト、およびGPR54活性の1以上のモジュレーターからなる群から選択される1以上を用いて患者を治療するステップを含んでなる上記方法。
- GPR54ポリペプチド、GPR54ポリペプチドの1以上のアゴニスト、GPR54ポリペプチドの1以上のアンタゴニスト、GPR54活性の1以上のモジュレーターからなる群から選択される1以上の化合物の、筋消耗性疾患、疼痛、炎症、ホルモン依存性癌、乳汁分泌、骨粗鬆症/大理石骨病、閉経に関係するホルモン不均衡、ならびに肥満からなる群から選択される患者の症状を予防または治療する医薬品の製造における使用。
- 患者の性ホルモン軸を操作する方法であって、治療上有効な量のGPR54ポリペプチド、GPR54ポリペプチドの1以上のアゴニスト、GPR54ポリペプチドの1以上のアンタゴニスト、およびGPR54活性の1以上のモジュレーターからなる群から選択される1以上を用いて患者を治療するステップを含んでなる上記方法。
- GPR54ポリペプチド、GPR54ポリペプチドの1以上のアゴニスト、GPR54ポリペプチドの1以上のアンタゴニスト、およびGPR54活性の1以上のモジュレーターからなる群から選択される化合物の、動物の性ホルモン軸を操作する医薬品の製造における使用。
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GB0320623A GB0320623D0 (en) | 2003-09-03 | 2003-09-03 | Harry Potter |
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US7754220B2 (en) | 2003-03-12 | 2010-07-13 | Takeda Pharmaceutical Company Limited | Methods of inhibiting secretion of follicle-stimulating hormone and testosterone |
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US8404643B2 (en) | 2005-12-22 | 2013-03-26 | Takeda Pharmaceutical Company Limited | Metastin derivatives and use thereof |
AR058584A1 (es) | 2005-12-22 | 2008-02-13 | Takeda Pharmaceutical | Derivados de metastina y uso de los mismos |
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