JP2001512492A - Lsr受容体、その活性、そのクローニングならびにその肥満および関連する危険性または合併症の診断、予防および/または治療への応用 - Google Patents
Lsr受容体、その活性、そのクローニングならびにその肥満および関連する危険性または合併症の診断、予防および/または治療への応用Info
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- JP2001512492A JP2001512492A JP51192099A JP51192099A JP2001512492A JP 2001512492 A JP2001512492 A JP 2001512492A JP 51192099 A JP51192099 A JP 51192099A JP 51192099 A JP51192099 A JP 51192099A JP 2001512492 A JP2001512492 A JP 2001512492A
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- lsr
- receptor
- seq
- nucleic acid
- polypeptide
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Abstract
Description
Claims (1)
- 【特許請求の範囲】 1. 遊離脂肪酸の存在下でリポタンパク質と結合でき、遊離脂肪酸の不在下 でサイトカインと結合できることを特徴とする、精製LSR受容体。 2. 肝臓と末梢組織、好ましくは脂肪組織、との間の脂質、特に食餌脂質の 分布を調整できる、請求項1記載の受容体。 3. サイトカインがレプチンである、請求項1または2記載の受容体。 4. タンパク質gC1q-Rまたはその類似タンパク質の1つと更に結合できる、 請求項1〜3のいずれか1項に記載の受容体。 5. 受容体が肝細胞受容体である、請求項1〜4のいずれか1項に記載の受容 体。 6. 結合したリポタンパク質が細胞内へ取り込まれ、次いで分解される、請 求項1〜5のいずれか1項に記載の受容体。 7. 結合したサイトカインが細胞内に取り込まれ、次いで分解される、請求 項1〜6のいずれか1項に記載の受容体。 8. 結合したリポタンパク質がアポタンパク質Bおよび/またはEを含む、請 求項1〜7のいずれか1項に記載の受容体。 9. 化合物C1qまたはその類似化合物の1つが受容体活性を調整できる、請 求項1〜8のいずれか1項に記載の受容体。 10. 化合物C1qまたはその類似化合物の1つが、遊離脂肪酸の不存下で、 受容体に結合するリポタンパク質の量を増加させ、および/または細胞が結合し たリポタンパク質の取り込みおよび分解を増加させることができる、請求項9記 載の受容体。 11. 約66kDaの分子量を有するサブユニットおよび約58kDaの分子量を有す るサブユニットの少なくとも1つを含んでなる、請求項1〜10のいずれか1項に 記載の受容体。 12. ラットまたはマウス受容体である、請求項11記載の受容体。 13. 約72kDaの分子量を有するサブユニットおよび約64kDaの分子量を有す るサブユニットの少なくとも1つを含んでなる、請求項1〜10のいずれか1項に 記載の受容体。 14. 精製ヒト受容体である請求項13記載の受容体。 15. 配列番号2のアミノ酸配列またはそれと相同な配列を含んでなるαサ ブユニット、または配列番号4のアミノ酸配列またはそれと相同な配列を含んで なるα'サブユニットと、配列番号6のアミノ酸配列またはそれと相同な配列を含 んでなる1つ、好ましくは3つのβサブユニットとを含む、請求項1〜12のいず れか1項に記載の受容体。 16. 配列番号16のアミノ酸配列またはそれと相同な配列を含んでなるαサ ブユニット、または配列番号17のアミノ酸配列またはそれと相同な配列を含んで なるα'サブユニットと、配列番号18のアミノ酸配列またはそれと相同な配列を 含んでなる1つ、好ましくは3つのβサブユニットとを含む、請求項1〜12のい ずれか1項に記載の受容体。 17. 配列番号8のアミノ酸配列またはそれと相同な配列を含んでなるαサ ブユニット、または配列番号10のアミノ酸配列またはそれと相同な配列を含んで なるα'サブユニットと、配列番号12のアミノ酸配列またはそれと相同な配列を 含んでなる1つ、好ましくは3つのβサブユニットとを含む、請求項1〜10およ び13および14のいずれか1項に記載の受容体。 18. 組換え受容体である、請求項1〜17のいずれか1項に記載の受容体。 19. 組換え宿主内で、ラット、マウスまたはヒトLSR受容体のαまたはα' サブユニットおよび1つ、好ましくは3つのβサブユニット、特に、αまたはα 'サブユニットおよび3つのβサブユニット、をコードする1以上のヌクレオチ ド 配列発現させることにより得られた組換え受容体である、請求項18記載の受容体 。 20. 請求項1〜19のいずれか1項に記載の受容体からなる、精製、単離ま たは組換えポリペプチド。 21. LSR受容体の少なくとも5、好ましくは少なくとも10〜15、の連続す るアミノ酸配列、およびそのポリペプチドの相同体、断片または変異体を含んで なる、請求項20のポリペプチド。 22. ラットLSR受容体、マウスLSR受容体、またはヒトLSR受容体の少なく とも10〜15のアミノ酸配列を含んでなる、請求項20または21に記載のポリペプチ ド。 23. 配列番号2、配列番号4および配列番号6の配列、およびそのポリペプ チドの変異体、等価体、または相同体、またはそれらの断片の1つ、好ましくは そのポリペプチドの相同体、または生物学的に活性な断片からなる群より選択さ れる配列の少なくとも10〜15の連続するアミノ酸配列を含んでなる、請求項20〜 22のいずれか1項に記載のポリペプチド。 24. 配列番号16、配列番号17および配列番号18の配列、およびそのポリペ プチドの変異体、等価体、または相同体、またはそれらの断片の1つ、好ましく はそのポリペプチドの相同体、または生物学的に活性な断片からなる群より選択 される配列の少なくとも10〜15の連続するアミノ酸配列を含んでなる、請求項20 〜22のいずれか1項に記載のポリペプチド。 25. 配列番号8、配列番号10および配列番号12の配列、およびそのポリペ プチドの変異体、等価体、または相同体、またはそれらの断片の1つ、好ましく はそのポリペプチドの相同体、または生物学的に活性な断片からなる群より選択 される配列の少なくとも10〜15の連続するアミノ酸配列を含んでなる、請求項20 〜22のいずれか1項に記載のポリペプチド。 26. 脂肪酸結合部位を含んでなる、請求項23〜25のいずれか1項に記載の ポリペプチド。 27. 脂肪酸結合部位が、アームが疎水性アミノ酸からなるヘアピン構造を 誘導する2つのアミノ酸により2つの部分に分けられる疎水性アミノ酸配列を含 んでなる、請求項26記載のポリペプチド。 28. クラスリン(clathrin)結合部位を含んでなる、請求項23〜25のいず れか1項に記載のポリペプチド。 29. トランスメンブランドメインを構成する疎水性領域を含んでなる、請 求項23〜25のいずれか1項に記載のポリペプチド。 30. 周縁膜系において、タンパク質のエンドサイトーシスおよび細胞内へ の接近を制御することができる領域を含んでなる、請求項23〜25のいずれか1項 に記載のポリペプチド。 31. モチーフLIおよびLLを含む部位を含んでなる周縁膜系において、タン パク質のエンドサイトーシスおよび細胞内への接近を制御することができる領域 を含んでなる、請求項30記載のポリペプチド。 32. サイトカイン結合部位を含んでなる、請求項23〜25のいずれか1項に 記載のポリペプチド。 33. サイトカイン結合部位がシステインリッチ領域を含んでなる、請求項 32記載のポリペプチド。 34. ApoBおよびApoEなどの可能性のあるアポタンパク質リガンドの結合部 位を決定する領域を含んでなる、請求項23〜25のいずれか1項に記載のポリペプ チド。 35. 可能性のあるアポタンパク質リガンドの結合部位を決定する領域が、 選択的に+および-の電荷を持つアミノ酸配列を含んでなる、請求項34記載のポリ ペプチド。 36. モチーフRSRSを含んでなる、請求項23〜25、34および35のいずれか1 項に記載のポリペプチド。 37. 請求項26〜36のいずれか1項に記載の部位、モチーフまたは領域の1 以上を含んでなる、請求項23〜25のいずれか1項に記載のポリペプチド。 38. 配列番号29および配列番号30の配列から選択される配列を含んでなる 、請求項23〜25のいずれか1項に記載のポリペプチド。 39. 請求項1〜38のいずれか1項に記載の受容体またはポリペプチドをコ ードする精製、単離または組換え核酸配列。 40. 配列番号19および配列番号41の配列、およびその変異体、等価体、相 同体、断片、およびその核酸と相補的な核酸配列から選択されるポリヌクレオチ ド配列の、少なくとも8、好ましくは少なくとも10、の連続するヌクレオチドを 含んでなることを特徴とする精製核酸。 41. 配列番号19のヌクレオチド1898〜21094、特にヌクレオチド2001〜209 79、さらに特にはヌクレオチド2145〜20979に相当する核酸配列、およびその変 異体、等価体、相同体、断片、およびその核酸と相補的な核酸配列を含んでなる ことを特徴とする、ヒトLSR受容体をコードする精製核酸。 42. エキソン、エキソンの組み合わせ、または1以上のエキソン部分にわ たって延びるポリヌクレオチドを含んでなる、請求項41記載の核酸。 43. 配列番号19のヌクレオチド1〜1897に相当する核酸配列、およびその 変異体、等価体、相同体、断片、およびその核酸と相補的な核酸配列を含んでな ることを特徴とする精製核酸。 44. 配列番号19のヌクレオチド21095〜22976に相当する核酸配列、および その変異体、等価体、相同体、断片、およびその核酸と相補的な核酸配列を含ん でなることを特徴とする精製核酸。 45. 配列番号7、配列番号9および配列番号11の配列、およびその変異体、 等価体、相同体、断片およびその核酸と相補的な核酸配列からなる群より選択さ れるヌクレオチド配列を含んでなることを特徴とする精製核酸。 46. 配列番号1、配列番号3および配列番号5の配列、およびその変異体、 等価体、相同体、断片およびその核酸と相補的な核酸配列からなる群より選択さ れるヌクレオチド配列を含んでなることを特徴とする精製核酸。 47. 配列番号13、配列番号14および配列番号15の配列、およびその変異体 、等価体、相同体、断片およびその核酸と相補的な核酸配列からなる群より選択 されるヌクレオチド配列を含んでなることを特徴とする精製核酸。 48. 配列番号19のヌクレオチド1898〜2001、または配列番号19のヌクレオ チド1898〜2144に相当する核酸配列、およびその変異体、等価体、相同体、断片 、およびその核酸と相補的な核酸配列を含んでなることを特徴とする精製核酸。 49. 配列番号19のヌクレオチド20980〜21094に相当する核酸配列、および その変異体、等価体、相同体、断片、およびその核酸と相補的な核酸配列を含ん でなることを特徴とする精製核酸。 50. 少なくとも95%の一致を保障するハイブリダイゼーション条件の下で 、配列番号1、配列番号3、配列番号5、配列番号7、配列番号9、配列番号11、配 列番号13、配列番号14および配列番号15からなる群より選択される核酸配列と特 異的にハイブリダイズできることを特徴とする、少なくとも8つのヌクレオチド を含んでなる核配列。 51. 配列の長さが、8、10、15、20または30〜200ヌクレオチド、さらに特 には20〜30ヌクレオチドと変化する、請求項50記載の核配列。 52. 請求項40〜51のいずれか1項に記載の核酸配列を含有するクローニン グおよび/または発現ベクター。 53. 請求項52記載のベクターで形質転換された宿主細胞。 54. 請求項53記載の細胞を含んでなる、ヒト以外の哺乳類。 55. マウス、ラットまたはウサギである、請求項54記載の哺乳類。 56. 核酸配列の検出および/または増幅用のプローブまたはプライマーと しての、請求項40〜51のいずれか1項に記載の核酸配列の使用。 57. 組換えまたは合成ポリペプチドの製造のための、請求項40〜51にいず れか1項に記載の核酸配列の使用。 58. 請求項53記載の形質転換細胞を、組換えポリペプチドの発現を可能に する条件下で培養し、その組換えポリペプチドを回収する、組換えポリペプチド の製造方法。 59. 請求項58記載の方法によって得られるポリペプチド。 60. 請求項20〜38のいずれか1項に記載のポリペプチドおよび/または請 求項1〜19のいずれか1項に記載の受容体を特異的に認識することができる、モ ノ-またはポリクローナル抗体、もしくはそれらの断片、キメラまたは免疫結合 抗体。 61. 請求項60記載の抗体を使用する、請求項20〜38のいずれか1項にポリ ペプチドの検出および/または精製方法。 62. 請求項58および61のいずれか1項に記載の方法により得られる精製ポ リペプチド。 63. 請求項40〜51のいずれか1項に記載の核酸配列を使用する対立遺伝子 の変異性、突然変異、欠失、異型接合性の欠如、または遺伝子の異常性の同定方 法。 64. 請求項20〜38のいずれか1項に記載のポリペプチドの異常な発現に関 連する症状および/または病因の診断方法であって、ポリペプチドと抗体または 抗体群との間での特異的な免疫複合体の形成を可能にする条件の下で、請求項60 の1以上の抗体を試験する生物学的材料と接触させ、形成された免疫複合体を検 出する方法。 65. 請求項1〜19のいずれか1項に記載のLSR受容体と相互作用可能な化学 化合物または生化学化合物を選択する方法であって、LSR受容体、LSR受容体発現 細胞、請求項53の細胞、請求項54または55の哺乳類、または請求項20〜38のいず れか1項に記載のポリペプチドを、LSR活性を修飾することができる候補化合物 と接触させ、次いで、LSR受容体活性の修飾、または候補化合物とLSR受容体、も しくはこのポリペプチドとの間の複合体の形成を直接的、あるいは間接的に検出 することを含んでなる方法。 66. 請求項26〜36のいずれか1項に記載のペプチドを、このペプチドの1 つと結合することができる候補化合物と接触させ、次いで、このペプチドと候補 化合物の間の複合体の形成の形成を検出することを含んでなる、請求項65記載の 方法。 67. 候補化合物がポリペプチド、ペプチド、脂肪酸、リポタンパク質、そ れらの誘導化合物、医薬および小分子の1つから選択される、請求項65記載の方 法。 68. ペプチドを支持体上に固定化する、請求項66記載の方法。 69. LSR受容体、LSR受容体発現細胞、請求項53の細胞、請求項54または55 の哺乳類、または請求項20〜38のいずれか1項に記載のポリペプチドを、LSRの 既知のリガンドと接触させ、次いで、この候補の、リガンドのLSRに結合する能 力との競合に介入する能力を決定することを含んでなる、請求項65記載の方法。 70. 脂肪酸およびリポタンパク質またはトリグリセリドの存在下で、候補 化合物をLSR受容体と接触させ、次いで、受容体によるリポタンパク質またはト リグリセリドの分解濃度を評価することを含んでなる、請求項65〜69のいずれか 1項に記載の方法。 71. LSR受容体のクラスリン結合部位と相互作用可能な候補化合物を、LSR 受容体、LSR受容体発現細胞、請求項28の哺乳類またはポリペプチドと接触させ 、次いで、LSR活性の修飾、または候補化合物とポリペプチドとの間の複合体の 形成を検出することを含んでなる、請求項65〜69のいずれか1項に記載の方法。 72. LSR受容体のトランスメンブランドメインを構成する疎水性領域と相 互作用可能な候補化合物を、LSR受容体、LSR受容体発現細胞、請求項29の哺乳類 またはポリペプチドと接触させ、次いで、LSR活性の修飾、または候補化合物と ポリペプチドとの間の複合体の形成を検出することを含んでなる、請求項65〜69 のいずれか1項に記載の方法。 73. 周縁膜系において、タンパク質のエンドサイトーシスおよび細胞内へ の接近を制御できるLSR受容領域と相互作用可能な候補化合物を、LSR受容体、LS R受容体発現細胞、請求項30または31の哺乳類またはポリペプチドと接触させ、 次いで、LSR活性の修飾、または候補化合物とポリペプチドとの間の複合体の形 成を検出することを含んでなる、請求項65〜69のいずれか1項に記載の方法。 74. サイトカイン結合部位と相互作用可能な候補化合物を、LSR受容体、L SR受容体発現細胞、請求項32または33の哺乳類またはポリペプチドと接触させ、 次いで、LSR活性の修飾、または候補化合物とポリペプチドとの間の複合体の形 成を検出することを含んでなる、請求項65〜69のいずれか1項に記載の方法。 75. 可能性あるApoBおよびl'ApoEなどのアポタンパク質の結合部位を決定 する領域と相互作用可能な候補化合物を、LSR受容体、LSR受容体発現細胞、請求 項34〜36のいずれか1項に記載の哺乳類またはポリペプチドと接触させ、次いで 、LSR活性の修飾、または候補化合物とポリペプチドとの間の複合体の形成を検 出することを含んでなる、請求項65〜69のいずれか1項に記載の方法。 76. 請求項1〜19のいずれか1項に記載の受容体の発現または活性、およ びこの受容体と、この受容体の活性に関与し得る化学または生化学化合物との間 の直接的、または間接的相互作用を試験するための、請求項53の細胞、請求項54 および55のいずれか1項に記載の哺乳類、または請求項20〜38のいずれか1項に 記載のポリペプチドの使用。 77. 請求項65〜75のいずれか1項に記載の方法により選択される、LSR受 容体と直接的、または間接的に相互作用可能な化合物。 78. LSR受容体の活性の調整用薬剤の調製のための、サイトカイン、特に レプチンの使用。 79. 請求項1〜19のいずれか1項に記載の受容体の数、それらの再生速度 、および/またはそれらの活性の特異性の調整を可能にする、請求項78記載の使 用。 80. 請求項1〜19のいずれか1項に記載の受容体と直接的、または間接的 に相互作用可能な化学または生化学化合物。 81. 請求項1〜19のいずれか1項に記載の受容体の発現または活性の調整 を可能にする化学または生化学化合物。 82. 請求項65〜75のいずれか1項に記載の方法により選択される、請求項 80および81のいずれか1項に記載の化合物。 83. 選択される化合物がレプチン、またはその誘導化合物の1つ、好まし くはそのタンパク質変異体の1つ、または、化学的に修飾されているか、もしく は遺伝子組換えによって得られるレプチン、またはそれらの断片である、請求項 80〜82のいずれか1項に記載の化合物。 84. 請求項1〜19のいずれか1項に記載の受容体の数、それらの再生速度 、および/またはそれらの活性の特異性の調整を可能にする、請求項80〜83のい ずれか1項に記載の化合物。 85. 請求項1〜19のいずれか1項に記載の受容体の総活性または発現の増 強、および/またはこの受容体のサイトカイン、特に、レプチンクリアランス活 性の特異的増強、および/またはこの受容体のリポタンパク質クリアランス活性 の特異的増強を可能にする、請求項80〜84のいずれか1項に記載の化合物。 86. 請求項1〜19のいずれか1項に記載の受容体の総活性または発現の低 減、および/またはこの受容体のサイトカイン、特に、レプチンクリアランス活 性の特異的低減、および/またはこの受容体のリポタンパク質クリアランス活性 の特異的低減を可能にする、請求項80〜85のいずれか1項に記載の化合物。 87. サイトカイン、特に、レプチンの排出の調整、および/またはリポタ ンパク質、カイロミクロン残留物および/またはトリグリセリドの排出の調整を 可能にする、請求項80〜86の少なくとも1項に記載の化合物。 88. サイトカイン濃度、特に、レプチン血症の調整、および/またはリポ タンパク質、カイロミクロン残留物および/またはトリグリセリドの濃度の調整 を可能にする、請求項80〜87のいずれか1項に記載の化合物。 89. サイトカイン濃度、特にレプチン血症の制御を可能にする、請求項80 〜88のいずれか1項に記載の化合物。 90. リポタンパク質濃度の制御、好ましくは低減、カイロミクロン残留物 の血漿濃度における低減、および/またはトリグリセリド血症の低減の制御を可 能にする請求項80〜89のいずれか1項に記載の化合物。 91. 請求項60の抗体、請求項20〜38のいずれか1項のポリペプチド;請求 項1〜19のいずれか1項の受容体の可溶性画分に相当する請求項20〜38のいずれ か1項のポリペプチド;化合物gC1qR、その類似タンパク質の1つ、その変異体 の1つ、またはそれらの断片の1つ;請求項52のベクター;肝細胞の特異的認識 に関する部位をその外表に有する請求項52のベクター;ベクターにより標的細胞 中へ挿入された核酸の発現生成物が、形質転換標的細胞につなぎ留められるか、 形質転換細胞により放出される、請求項52のベクター;センスまたはアンチセン ス核酸配列;レプチン、またはそのタンパク質変異体の1つ、または化学修飾さ れているか、または遺伝子組換えにより修飾されているレプチン、またはそれら の断片の1つから選択される、請求項80〜90のいずれか1項に記載の化合物。 92. 医薬としての、請求項80〜91のいずれか1項に記載の化合物。 93. 食餌習慣における障害に関連する病状および/または病因の予防およ び/または治療に用いられる、請求項92記載の化合物。 94. サイトカインの代謝における障害に関連する病状および/または病因 の予防および/または治療に用いられる、請求項92記載の化合物。 95. 肥満または食欲不振の予防および/または治療に用いられる、請求項 92〜94のいずれか1項に記載の化合物。 96. 肥満に伴う、あるいは肥満により引き起こされる病状および/または 病因の予防および/または治療に用いられる、請求項92〜95のいずれか1項に記 載の化合物。 97. 心不全、冠状動脈不全、脳血管障害、アテローム性疾患、アテローム 性動脈硬化症、高血圧症、非インスリン依存性糖尿病、高脂肪血症、および/ま たは高尿酸血症の予防および/または治療に用いられる、請求項96記載の化合物 。 98. アテローム性疾患および/またはアテローム性動脈硬化症の予防およ び/または治療用の、請求項97記載の化合物。 99. 請求項52のベクター;肝細胞の特異的に認識に関する部位をその外部 に有する請求項52のベクター;ベクターにより標的細胞中へ挿入された核酸の発 現生成物が、形質転換標的細胞につなぎ留められているか、または形質転換細胞 により放出される、請求項52のベクター;食餌習慣における疾患、肥満に関連す る病状および/または病因、および/または肥満に伴う、あるいは肥満により引 き起こされる病状および/または病因の遺伝子治療による予防および/または治 療用センスまたはアンチセンス核酸配列から選択される、請求項80〜90のいずれ か1項に記載の化合物。
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FR9710088A FR2767136B1 (fr) | 1997-08-06 | 1997-08-06 | Recepteur complexe lsr, activite, clonage, et applications au diagnostic, a la prevention et/ou au traitement de l'obesite et des risques ou complications associes |
FR97/10088 | 1997-08-06 | ||
FR98/05032 | 1998-04-22 | ||
FR9805032A FR2767135B1 (fr) | 1997-08-06 | 1998-04-22 | Recepteur complexe lsr, activite, clonage, et application au diagnostic, a la prevention et/ou au traitement de d'obesite et des risques ou complications associes |
PCT/IB1998/001257 WO1999007737A2 (fr) | 1997-08-06 | 1998-08-06 | Recepteur lsr, clonage et applications |
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JP2010248094A (ja) * | 2009-04-13 | 2010-11-04 | Kobe Univ | タイトジャンクション調節因子 |
KR20140029446A (ko) * | 2011-04-15 | 2014-03-10 | 컴퓨젠 엘티디. | 면역 관련 장애 및 암의 치료를 위한 폴리펩티드 및 폴리뉴클레오티드, 및 이들의 용도 |
JP2014517685A (ja) * | 2011-04-15 | 2014-07-24 | コンピュゲン エルティーディー. | 免疫関連疾患およびがんの治療のためのポリペプチドおよびポリヌクレオチドならびにそれらの使用 |
JP2017200908A (ja) * | 2011-04-15 | 2017-11-09 | コンピュゲン エルティーディー. | 免疫関連疾患およびがんの治療のためのポリペプチドおよびポリヌクレオチドならびにそれらの使用 |
JP2015532587A (ja) * | 2012-06-21 | 2015-11-12 | コンピュゲン エルティーディー. | Lsr抗体およびがんの治療のためのその使用 |
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