JP5855849B2 - 新規ヒアルロン酸分解促進因子及びその阻害剤 - Google Patents
新規ヒアルロン酸分解促進因子及びその阻害剤 Download PDFInfo
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- JP5855849B2 JP5855849B2 JP2011125167A JP2011125167A JP5855849B2 JP 5855849 B2 JP5855849 B2 JP 5855849B2 JP 2011125167 A JP2011125167 A JP 2011125167A JP 2011125167 A JP2011125167 A JP 2011125167A JP 5855849 B2 JP5855849 B2 JP 5855849B2
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Description
すなわち、本発明は、KIAA1199のヒアルロン酸分解促進機能とその阻害に関する。
1つの形態において、前記スクリーニング方法は、KIAA1199遺伝子又はKIAA1199遺伝子によってコードされるタンパクの発現量を指標として、被験物質のヒアルロン酸分解制御効果を評価する。
1)細胞を被験物質の存在又は非存在下で培養する;
2)上記細胞のKIAA1199遺伝子又はKIAA1199遺伝子によってコードされるタンパクの発現量を測定する;
3)被験物質の存在及び非存在下における、上記遺伝子又はタンパクの発現量の相違に基づき、当該被験物質のヒアルロン酸分解制御効果を評価する。
前記方法は、たとえば、下記の工程を含む:
1)KIAA1199遺伝子を一過性又は安定的に高発現している細胞を、標識ヒアルロン酸の共存下で、被験物質の存在又は非存在下で培養する;
2)培養後の培養上清を回収し、標識ヒアルロン酸の分子量を測定する;
3)被験物質の存在及び非存在下における、標識ヒアルロン酸の分子量の相違に基づき、当該被験物質のヒアルロン酸分解制御効果を評価する。
i) KIAA1199遺伝子に対するアンチセンス核酸又はsiRNA、
ii) KIAA1199遺伝子によってコードされるタンパクに特異的な抗体、又は
iii) クロルプロマジン、N−エチルマレイミド、バフィロマイシンA1、モネンシン、EDTA、デフェロキサミン、及びオリエンチンから選ばれる低分子化合物を適用(投与、導入)する工程を含む。
i) KIAA1199遺伝子
ii) KIAA1199遺伝子によってコードされるタンパク、又は
iii) KIAA1199遺伝子又はKIAA1199遺伝子によってコードされるタンパクの発現又は活性を促進させる物質、を適用(投与、導入)する工程を含む。
i) KIAA1199遺伝子に対するアンチセンス核酸又はsiRNA
ii) KIAA1199遺伝子によってコードされるタンパクに特異的な抗体、又は
iii) クロルプロマジン、N−エチルマレイミド、バフィロマイシンA1、モネンシン、EDTA、デフェロキサミン、及びオリエンチンから選ばれる低分子化合物、を含む。
i) KIAA1199遺伝子
ii) KIAA1199遺伝子によってコードされるタンパク、もしくは
iii) KIAA1199遺伝子又はKIAA1199遺伝子によってコードされるタンパクの発現又は活性を促進させる物質、を含む。
(a)KIAA1199遺伝子を一過性又は安定的に高発現している細胞
(b)KIAA1199遺伝子によってコードされるタンパクに特異的なモノクローナル抗体
(c)KIAA1199遺伝子を特異的に増幅するためのオリゴヌクレオチドプライマー
(d)KIAA1199遺伝子に特異的に結合し、該遺伝子を検出するためのポリヌクレオチドプローブ
以下、本発明について詳細に説明する。
本発明にかかる「KIAA1199遺伝子」とは、遺伝子シンボル(Gene Symbol)KIAA1199で示される機能未知の遺伝子断片(EST)であり、TMEM2Lと記載されることもある。
アンチセンス核酸
「アンチセンス核酸」とは、標的核酸に対して相補的あるいは実質的に相補的な塩基配列又はその一部を含有する核酸であって、前記標的核酸のmRNAの少なくとも一部(標的部位)にハイブリダイズし、その発現を抑制する機能を有する核酸である。ここで「実質的に相補的」とは、標的部位にハイブリダイズし、標的核酸の発現を抑制できる限りにおいて、部分的ミスマッチを許容することを意味する。具体的には、「実質的に相補的」な配列とは、標的部位の配列に対して70%以上、好ましくは80%以上、より好ましくは90%以上、さらに好ましくは95%以上の配列を言う。
「siRNA(small interfering RNA)」は、細胞に2本鎖RNA(dsRNA)が取り込まれると、相補的なmRNAが分解されるRNA干渉を利用して、標的核酸の発現を抑制する小分子RNAである。
本発明で用いられる「KIAA1199遺伝子によってコードされるタンパクに特異的な抗体(抗KIAA1199抗体)」は、公知の方法にしたがって調製することができる。すなわち、常法により、抗原となるKIAA1199タンパク、あるいはその任意の部分ポリペプチドを用いて動物を免疫し、該動物生体内に産生される抗体を採取、精製することによって得ることができる。
発明者らは、とくに配列表の配列番号3〜5のいずれかで示されるアミノ酸配列を有するペプチドをエピトープとして作製したモノクローナル抗体が高い特異性を有し、優れたKIAA1199抑制効果を有することを確認した。本発明は、この配列番号3〜5で示される「KIAA1199エピトープペプチド」も提供する。
本発明にかかる「ヒアルロン酸分解制御剤」とは、KIAA1199遺伝子又はKIAA1199タンパクの発現や活性を制御することにより、KIAA1199を介したヒアルロン酸の分解を制御(阻害又は促進)する物質あるいは調製物である。すなわち、本発明において、「ヒアルロン酸分解制御剤」は、以下に説明する「ヒアルロン酸分解阻害剤」と「ヒアルロン酸分解促進剤」の両方を包含する。
本発明にかかる「ヒアルロン酸分解阻害剤」とは、KIAA1199遺伝子又はKIAA1199タンパクの発現や活性を抑制することにより、KIAA1199を介したヒアルロン酸の分解を阻害する物質あるいは調製物である。
「ヒアルロン酸の異常分解を伴う症状あるいは疾患」とは、ヒアルロン酸分解が生理的に正常時より亢進している症状又は疾患であって、具体的にはヒアルロン酸の分解が患部で異常亢進しているリウマチ、変形性関節症、乾癬性関節症、痛風、多発性関節炎、外傷性関節炎などの関節症、肝炎、歯肉炎、及び癌等の悪性腫瘍が挙げられる。また血清中でヒアルロン酸量が増大していることから患部でヒアルロン酸の分解が異常に亢進していると考えられる肝硬変、移植拒否、乾癬及び強皮症、また疾患によって臓器が硬化する肝硬変、動脈硬化等の線維症、さらにはヒアルロン酸分解の結果として患部で水分保持能力が低下している乾皮症、乾燥肌、荒れ肌、その他腎炎、ケロイド、過修復、敗血症等の疾患も含まれる。本発明のヒアルロン酸分解阻害剤は、これらの症状や疾患に対して、疾患の症状を取り去るいわゆる治療剤のほか、その症状を軽減する改善剤、症状が現れるのを防止する予防剤として適用することができる。
ヒアルロン酸は、細胞と細胞の間、とりわけ皮膚の真皮に多く含まれ、皮膚の保湿や弾力性に寄与し、加齢に伴うその減少・枯渇は皮膚の乾燥やしわ形成につながる。それゆえ、本発明の「ヒアルロン酸分解阻害剤」は、ヒアルロン酸の分解に伴うシワ形成等を防止する組織修復薬として機能する。
変形性関節炎や関節リウマチなどの疾患においては、ヒアルロン酸の合成と分解のバランスが崩れ、滑膜内のヒアルロン酸が枯渇、低分子量化することが関節機能の低下をもたらす一因であることが知られている。本発明の「ヒアルロン酸分解阻害剤」は、こうした疾患状態におけるヒアルロン酸の分解を抑制して関節機能の低下を抑制する、関節機能改善薬として機能する。なお、関節機能改善には、軟骨の変性変化、滑膜の炎症、疼痛の抑制など、関節機能に関連するすべての症状の改善を含む。
乳癌、胃癌、結腸直腸癌など種々の癌細胞・組織において、KIAA1199遺伝子が高発現していることが知られ、抗癌剤投与によりその発現が低下することも報告されている。
また、多くの癌組織においてヒアルロン酸の産生と分解レベルの増加が癌の進展と関連していること、癌の侵潤・転移には癌細胞が産生するヒアルロン酸と、同時に低分子化されたヒアルロン酸が関与し、これらのヒアルロン酸によって促進されることが知られている。
本発明の「ヒアルロン酸分解阻害剤」は、皮膚のヒアルロン酸の分解を阻害することにより、肌荒れや小ジワ、かさつきを防止する化粧料として利用することができる。
本発明にかかる「ヒアルロン酸分解促進剤」とは、KIAA1199遺伝子又はKIAA1199タンパクの発現や活性を促進することにより、KIAA1199を介したヒアルロン酸の分解を促進する物質あるいは調製物である。
「ヒアルロン酸の異常産生亢進を伴う症状あるいは疾患」とは、ヒアルロン酸合成が生理的に正常時より亢進している症状又は疾患であって、具体的には、乾癬、動脈硬化、骨異常形成、心筋梗塞等が挙げられる。「ヒアルロン酸の異常分解抑制を伴う症状あるいは疾患」とは、ヒアルロン酸分解が正常時より抑制されている症状又は疾患であって、具体的には、ヒアルロン酸の分解が患部で異常抑制されていると考える脱毛症、若はげ等が挙げられる。
本発明のヒアルロン酸分解促進剤は、これらの症状や疾患に対して、疾患の症状を取り去るいわゆる治療剤のほか、その症状を軽減する改善剤、症状が現れるのを防止する予防剤として適用することができる。
ヒアルロン酸局所投与製剤を用いた美容医療(組織修復)においては、注入部位の補正として、ヒアルロン酸分解酵素を投与する。本発明の「ヒアルロン酸分解促進剤」は、こうしたヒアルロン酸による組織修復の補正(余分な注入ヒアルロン酸の分解)用として利用することができる。
発明者らは、非症候性難聴患者でみられる変異KIAA1199タンパクが、KIAA1199を介したヒアルロン酸分解機能にも損傷がみられることを確認した。このことは、非症候性難聴の発症とKIAA1199を介したヒアルロン酸分解には何らかの関連があり、KIAA1199の活性又は発現を促進させることにより、難聴の発症を抑制し、症状を改善しうる可能性を示唆する。すなわち、「ヒアルロン酸分解促進剤」は、こうした難聴の予防・治療用として利用することができる。
本発明は、「ヒアルロン酸又はその薬理学的に許容されうる塩もしくは誘導体と、本発明のヒアルロン酸分解阻害剤とを含む局所投与用製剤」を提供する。
本発明は、KIAA1199を標的とするヒアルロン酸分解制御剤のスクリーニング方法も提供する。具体的には、被験物質によるKIAA1199遺伝子又はKIAA1199タンパクの発現量の増減を指標として、当該被験物質のヒアルロン酸分解制御効果を評価するか、あるいは外部より添加したヒアルロン酸の分子量を指標として評価する。
KIAA1199遺伝子又はKIAA1199タンパクの発現量を指標として評価する方法は、たとえば下記のように実施する:
1)細胞を被験物質の存在又は非存在下で培養する;
2)上記細胞のKIAA1199遺伝子又はKIAA1199タンパクの発現量を測定する;
3)被験物質の存在及び非存在下における、上記遺伝子又はタンパクの発現量の相違に基づき、当該被験物質のヒアルロン酸分解制御効果を評価する。
本発明のスクリーニング方法で用いられる細胞は、KIAA1199を一過性あるいは安定的に高発現している細胞であれば特に限定されず、線維芽細胞、滑膜細胞等を選択することができる。なお、「安定的に高発現する」とは、KIAA1199に対する被験物質の作用が十分評価できる程度に該KIAA1199遺伝子あるいはタンパクが高レベルで発現していることを意味する。
KIAA1199遺伝子発現量は、回収した細胞からまず全RNAを抽出し、この全RNA中におけるKIAA1199遺伝子(mRNA)の発現量を後述するいずれかの方法を用いて測定する。
KIAA1199タンパク発現量は、たとえば抗原抗体反応を利用した免疫学的方法を用いて測定することができる。
評価は、被験物質の存在下(投与条件下)でのKIAA1199遺伝子又はKIAA1199タンパク発現量と非存在下での発現量を比較して行ってもよいし、標準となるKIAA1199遺伝子又はKIAA1199タンパク発現量の基準値が決定されれば、その基準値と被験物質存在下におけるKIAA1199遺伝子又はKIAA1199タンパク発現量を比較することにより行ってもよい。
KIAA1199を介したヒアルロン酸分解を、ヒアルロン酸の分子量を指標として評価する場合は、たとえば下記のように実施する:
1)KIAA1199遺伝子を一過性又は安定的に高発現している細胞を、標識ヒアルロン酸の共存下、被験物質の存在下又は非存在下で培養する;
2)培養後の培養上清を回収し、ゲル濾過カラムにて標識ヒアルロン酸の分子量を測定する;
3)被験物質の存在及び非存在下における、標識ヒアルロン酸の分子量の相違に基づき、当該被験物質のヒアルロン酸分解制御効果を評価する。
本発明は、ヒアルロン酸分解制御効果を評価するためのキットも提供する。
前記キットは、必須の構成要素として、以下の(a)〜(d)の少なくとも1つを含む。
(a)KIAA1199遺伝子を一過性又は安定的に高発現している細胞
(b)KIAA1199遺伝子によってコードされるタンパクに特異的なモノクローナル抗体
(c)KIAA1199遺伝子を特異的に増幅するためのオリゴヌクレオチドプライマー
(d)KIAA1199遺伝子に特異的に結合し、該遺伝子を検出するためのポリヌクレオチドプローブ
KIAA1199遺伝子を一過性又は安定的に高発現している細胞は、前項に記載した方法によって調製することができる。細胞は、KIAA1199遺伝子を強制発現させた組換え細胞であってもよい。
抗KIAA1199モノクローナル抗体(KIAA1199遺伝子によってコードされるタンパクに特異的なモノクローナル抗体)は、配列表の配列番号3〜5のいずれかで示されるアミノ酸配列、又は前記配列と配列同一性90%以上のアミノ酸配列を有するエピトープペプチドに特異的な抗体であることが好ましい。
KIAA1199遺伝子増幅用プライマーは、KIAA1199遺伝子の少なくとも一部に相補的な配列を有する5〜30塩基長の連続したオリゴヌクレオチドである。プライマーはKIAA1199遺伝子増幅用の塩基配列(配列番号1)に基づき、市販のプライマー設計ソフトを用いるなど、常法にしたがい容易に設計し、増幅させて調製することができる。このようなプライマーの例としては、配列表の配列番号9〜13に記載の塩基配列を有するオリゴヌクレオチドを挙げることができる。
KIAA1199遺伝子検出用プローブは、KIAA1199遺伝子に特異的にハイブリダイズするポリヌクレオチドであって、20〜1500塩基長程度のものが好ましい。具体的には、ノーザンハイブリダイゼーション法であれば、20塩基長程度の1本鎖オリゴヌクレオチドか2本鎖DNAが好適に用いられる。また、マイクロアレイであれば、100〜1500塩基長程度の2本鎖DNA、又は20〜100塩基長程度の1本鎖オリゴヌクレオチドが好適に用いられる。Affimetrix社のGene Chipシステムの場合は、25塩基長程度の1本鎖オリゴがよい。これらは、特にKIAA1199遺伝子の3’非翻訳領域に存在する配列特異性が高い部分に特異的にハイブリダイズするプローブとして設計することが好ましい。このようなプローブの例としては、配列表の配列番号14〜16に記載の塩基配列を有するオリゴヌクレオチドを挙げることができる。
細胞培養
正常ヒト皮膚線維芽細胞(Detroit 551、ATCC(American Type Culture Collection)、HS-27、NHDF)は、必須アミノ酸、1mMピルビン酸ナトリウム及び10%(vol/vol)ウシ胎児血清(FBS)(JRH Biosciences、Kansas)を補ったイーグル最小必須培地(MEM)(MP Biomedicals、Solon、OH)中で培養した。HEK293、COS-7細胞株及びヒト滑膜線維芽細胞(TOYOBO)は、10%ウシ胎児血清、100単位/mlペニシリン及び100μg/mlストレプトマイシンを添加したダルベッコ改変イーグル培地(Sigma)中で維持した。培養は、5%CO2を含有する加湿雰囲気中において37℃で行った。
[3H]標識ヒアルロン酸([3H]HA)は、Underhill及びTooleら(C. B. Underhill and B. P. Toole, Binding of hyaluronate to the surface of cultured cells. J. Cell Biol. 82 (1979) 475-84.)の方法に若干の改変を加えて調製した。簡潔に言えば、コンフルエントなDetroit 551線維芽細胞を、10μCi/mlのD-[1,6-3H(N)]グルコサミン塩酸塩と共にインキュベートした。馴化培地をプールし、プロナーゼ(0.3mg/ml)で消化し、エタノールで沈澱させた。生成したペレットを水に懸濁し、1.5%塩化セチルピリジニウム及び0.03M NaClを用いて再沈澱させた。生成したペレットを0.1%塩化セチルピリジニウム及び0.4M NaCl中に溶解させ、エタノールで再び沈澱させた。生成したペレットを5mMリン酸緩衝液(pH7.5)中に懸濁し、0.5%NaClで平衡化したセファロースCL-2Bカラム(10×600mm)に添加した。Vo画分を収集し、エタノールで沈澱させ、最後に、5mMリン酸緩衝液(pH7.5)中に溶解させた。
[3H]HA(40,000dpm/ml)を含有する培地中で、細胞をコンフルエントになるまで培養した。インキュベーション後、培地を回収し、セファロースCL-2Bカラム(10×600mm)に添加し、流速0.65ml/分で0.5%NaClで溶出し、各々2.55mlの画分を収集した。各画分の放射活性を測定した。
ヒトKIAA1199に対するラットモノクローナル抗体を、常法に従って作製した。抗ヒトHYAL2ポリクローナル抗体は、Harada及びTakahashiら(Hosami Harada and Masaaki Takahashi, CD44-dependent intracellular and extracellular catabolism of hyaluronic acid by hyaluronidase-1 and -2. J. Biol. Chem., 282 (2007) 5597-5607)の方法によって作製した。これらの特異的抗体は、免疫ペプチドを使用してアフィニティー精製した。抗CD44抗体及びGAPDH抗体は、Santa Cruz Biotechnology(Santa Cruz、CA)から購入した。
CDRFDTYRSKKESER(配列番号3)
CARYSPHQDADPLKPRE(配列番号4)
CDKVEQSYPGRSHYY(配列番号5)
ヒトKIAA1199、HYAL1及びHYAL2のcDNAをPCR増幅し、DNA配列決定によってcDNA配列を確認した。増幅したcDNAは、それぞれ、発現ベクターpcDNA3.1(-)(Invitrogen)に挿入した。一過性導入は、Lipofectamine LTX(Invitrogen、Carlsbad、CA)を使用して行った。
G418を含有する培地中で細胞を培養することによって安定な形質転換体を選択し、ウェスタンブロット及び細胞による[3H]HAの分解アッセイによって、KIAA1199の発現を確認した。
KIAA1199、HYAL2、CD44及び陰性対照に対する各25塩基のsiRNA(末端TT2塩基突出、修飾ナシ)は、Invitrogen(Carlsbad、CA)から入手した。siRNAの導入は、Lipofectamine RNAiMAX(Invitrogen、Carlsbad、CA)を使用して行った。
5’-AAACAUUGAAAUAUUCGCCAUGCUC(配列番号6)
5’-UUGACAAGGAGGCCAAGACAGUGGU(配列番号7)
5’-UUCAGCUUCAGGAACAACAGCCCUG(配列番号8)
ウェスタンブロットは、標準的な方法にしたがって実施した。リアルタイムPCRは、RNeasy(Qiagen)を用いて全RNAを分離し、High Capacity cDNA Archiveキット(Applied Biosystems、Foster City、CA)を用いてcDNA合成を行った。リアルタイムPCRは、TaqMan(登録商標)技術及びABI Prism 7700装置(Applied Biosystems、Foster City、CA)を用いて行った。
Forward(1): 5’-accatcagctggctcactct-3’(配列番号9)
Reverse(1): 5’-tgtccatgcaactcaagagc-3’(配列番号10)
Forward(2): 5’-gtgggttcaagacgtggagt-3’(配列番号11)
Reverse(2): 5’-tctatctcctccccgatgtg-3’(配列番号12)
Forward(3): 5’- accatcagctggctcactct-3’(forward(1)と同配列:配列番号9)
Reverse(3): 5’-cctcctttaccaaccccaat-3’(配列番号13)
フルオレセインアミンで標識された(FA-)HA、コンドロイチン硫酸A、コンドロイチン硫酸D、コンドロイチン硫酸E、デルマタン硫酸、ヘパリン及びヘパラン硫酸を含有する培地(PG Research)中で細胞を培養した。インキュベーションの後、培地を回収し、PBSで平衡化したセファロースCL-6Bカラム(10×35mm)に添加した。0.4ml/分で各々1.6mlの画分を収集し、蛍光(励起、490nm;発光、525nm)を測定した。分解したFA-HAの分子量は、同一条件下のFA-コンドロイチン硫酸D及びコンドロイチン硫酸E、ヘパリン及びヘパラン硫酸によって推定した。分解した[3H]HAの非還元末端の糖は、β-N‐アセチルグルコサミニダーゼとの糖鎖のインキュベーションの後、又はβ-グルクロニダーゼ消化後にβ-N-アセチルグルコサミニダーゼ消化を行った後、セファデックスG-25カラム(1×107cm)でのゲル濾過により同定した。
細胞を、指示されている濃度の阻害剤と共に3時間インキュベートし、それに続いて、阻害剤の存在下で[3H]HAと共に6時間インキュベートした。
1.ヒアルロン酸分解因子KIAA11199の同定
(1)培養ヒト正常線維芽細胞におけるヒアルロン酸分解系
まず、現在提唱されているHYAL1、HYAL2及びCD44(HA受容体)を介したヒアルロン酸の分解モデルが正常細胞において実際に機能するか否かを培養ヒト正常線維芽細胞を用いて調べた。
HYAL1、HYAL2及びCD44のうち、HYAL2とCD44の発現は培養線維芽細胞で検出されたが、siRNAを用いたHYAL2及びCD44のノックダウンは、ヒアルロン酸の分解に影響を与えなかった(図1b)。これらの結果は、培養線維芽細胞におけるヒアルロン酸分解機構は、HYAL酵素及びCD44に依存しないものであることを示唆した。
(1)KIAA1199によるHA分解
KIAA1199の役割を調べるために、HEK293細胞(ヒト胎児腎細胞)にKIAA1199全長cDNAを導入した。KIAA1199を一過性に発現するHEK293細胞は、培養皮膚線維芽細胞と同様に外部から添加したヒアルロン酸を分解した(図2a)。対照的に、空ベクターを導入した細胞は、ヒアルロン酸を分解しなかった(図2a)。類似の結果は、COS-7細胞(サル腎線維芽細胞)でも確認された(図2a)。以上の結果は、KIAA1199がヒアルロン酸分解機構にとって必須の因子であることを示唆する。
高頻度優性難聴を示す非症候性難聴患者において、アミノ酸置換を伴うKIAA1199の変異(R187C、R187H、H783R又はV1109I)が見出され、これが難聴の原因となりうることが報告されている(前掲)。
KIAA1199を介したヒアルロン酸分解機構をさらに検討するために、我々は、KIAA1199を安定的に発現するHEK293細胞株(KIAA1199/HEK293)を樹立した。培養KIAA1199/HEK293細胞は、外部から添加したコンドロイチン硫酸A、D、E、デルマタン硫酸、ヘパリン又はヘパラン硫酸を、ヒアルロン酸と異なり消化しなかった(図3a)。分解されたヒアルロン酸の分子量は、約15kDaと推定され(図3b)、その還元及び非還元末端は、それぞれN-アセチルグルコサミン及びグルクロン酸であった。
変形性関節症(OA)及び関節リウマチ(RA)の滑液は、正常な膝関節の滑液と比較して、低分子量、低濃度のヒアルロン酸を多く含有することが知られている。
配列番号4−ヒトKIAA1199エピトープペプチド(2)
配列番号5−ヒトKIAA1199エピトープペプチド(3)
配列番号6−ヒトKIAA1199 siRNA(1)
配列番号7−ヒトKIAA1199 siRNA(2)
配列番号8−ヒトKIAA1199 siRNA(3)
配列番号9−ヒトKIAA1199増幅用プライマー(Forward(1),Forward(3))
配列番号10−ヒトKIAA1199増幅用プライマー(Reverse(1))
配列番号11−ヒトKIAA1199増幅用プライマー(Forward(2))
配列番号12−ヒトKIAA1199増幅用プライマー(Reverse(2))
配列番号13−ヒトKIAA1199増幅用プライマー(Reverse(3))
配列番号14−ヒトKIAA1199検出用プローブ(1)
配列番号15−ヒトKIAA1199検出用プローブ(2)
配列番号16−ヒトKIAA1199検出用プローブ(3)
Claims (21)
- KIAA1199遺伝子を一過性又は安定的に高発現している細胞を用いて、被験物質のヒアルロン酸分解制御効果を評価することを特徴とする、ヒアルロン酸分解制御剤のスクリーニング方法。
- KIAA1199遺伝子又はKIAA1199遺伝子によってコードされるタンパクの発現量を指標として、被験物質のヒアルロン酸分解制御効果を評価することを特徴とする、請求項1記載の方法。
- 下記の工程を含む、請求項1記載の方法:
1)細胞を被験物質の存在又は非存在下で培養する;
2)上記細胞のKIAA1199遺伝子又はKIAA1199遺伝子によってコードされるタンパクの発現量を測定する;
3)被験物質の存在及び非存在下における、上記遺伝子又はタンパクの発現量の相違に基づき、当該被験物質のヒアルロン酸分解制御効果を評価する。 - 下記の工程を含む、請求項1記載の方法:
1)細胞を、標識ヒアルロン酸の共存下、被験物質の存在又は非存在下で培養する;
2)培養後の培養上清を回収し、標識ヒアルロン酸の分子量を測定する;
3)被験物質の存在及び非存在下における、標識ヒアルロン酸の分子量の相違に基づき、当該被験物質のヒアルロン酸分解制御効果を評価する。 - 細胞がKIAA1199遺伝子を強制発現させた組換え細胞である、請求項1〜4のいずれか1項に記載の方法。
- KIAA1199遺伝子又はKIAA1199遺伝子によってコードされるタンパクの発現又は活性を調節する物質を含み、かつ化粧料である、ヒアルロン酸分解制御剤。
- i) KIAA1199遺伝子に対するアンチセンス核酸又はsiRNA
ii) KIAA1199遺伝子によってコードされるタンパクに特異的な抗体、又は
iii) クロルプロマジン、N−エチルマレイミド、バフィロマイシンA1、モネンシン、EDTA、デフェロキサミン、及びオリエンチンから選ばれる低分子化合物、
を含む、請求項6記載のヒアルロン酸分解制御剤。 - 前記siRNAが、配列表の配列番号6〜8のいずれかで示される塩基配列、又は前記配列と配列同一性90%以上の塩基配列を有するものである、請求項7記載のヒアルロン酸分解制御剤。
- 前記抗体が、配列表の配列番号3〜5のいずれかで示されるアミノ酸配列、又は前記配列と配列同一性90%以上のアミノ酸配列を有するペプチドに特異的な抗体である、請求項7記載のヒアルロン酸分解制御剤。
- 関節機能改善、組織修復、又は荒れ肌、乾燥肌もしくは小ジワ改善のためのものである、請求項7〜9のいずれか1項記載のヒアルロン酸分解制御剤。
- i) KIAA1199遺伝子
ii) KIAA1199遺伝子によってコードされるタンパク、もしくは
iii) KIAA1199遺伝子又はKIAA1199遺伝子によってコードされるタンパクの発現又は活性を促進させる物質、
を含む、請求項6記載のヒアルロン酸分解制御剤。 - ヒアルロン酸による組織修復の補正に用いられるものである、請求項11記載のヒアルロン酸分解制御剤。
- ヒアルロン酸又はその薬理学的に許容されうる塩もしくは誘導体とヒアルロン酸分解制御剤とを含み、
該ヒアルロン酸分解制御剤が以下:
i) KIAA1199遺伝子に対するアンチセンス核酸又はsiRNA;
ii) KIAA1199遺伝子によってコードされるタンパクに特異的な抗体;又は
iii) クロルプロマジン、N−エチルマレイミド、バフィロマイシンA1、モネンシン、EDTA、デフェロキサミン、及びオリエンチンから選ばれる低分子化合物、
を含む、
局所投与用製剤。 - 前記siRNAが、配列表の配列番号6〜8のいずれかで示される塩基配列、又は前記配列と配列同一性90%以上の塩基配列を有するものである、請求項13記載の局所投与用製剤。
- 前記抗体が、配列表の配列番号3〜5のいずれかで示されるアミノ酸配列、又は前記配列と配列同一性90%以上のアミノ酸配列を有するペプチドに特異的な抗体である、請求項13記載の局所投与用製剤。
- 関節機能改善、組織修復、又は荒れ肌、乾燥肌もしくは小ジワ改善のためのものである、請求項13〜15のいずれか1項記載の局所投与用製剤。
- 関節機能改善薬又は組織修復薬である、請求項13〜16のいずれか1項記載の局所投与用製剤。
- 化粧料である、請求項13〜16のいずれか1項記載の局所投与用製剤。
- 以下の(a)〜(d)の少なくとも1つを含むヒアルロン酸分解制御効果評価用キット:
(a)KIAA1199遺伝子を一過性又は安定的に高発現している細胞
(b)KIAA1199遺伝子によってコードされるタンパクに特異的なモノクローナル抗体
(c)KIAA1199遺伝子を特異的に増幅するためのオリゴヌクレオチドプライマー
(d)KIAA1199遺伝子に特異的に結合し、該遺伝子を検出するためのポリヌクレオチドプローブ。 - モノクローナル抗体が、配列表の配列番号3〜5のいずれかで示されるアミノ酸配列、又は前記配列と配列同一性90%以上のアミノ酸配列を有するペプチドに特異的な抗体である、請求項19記載のキット。
- i) KIAA1199遺伝子
ii) KIAA1199遺伝子によってコードされるタンパク、もしくは
iii) KIAA1199遺伝子又はKIAA1199遺伝子によってコードされるタンパクの発現又は活性を促進させる物質、
を含むヒアルロン酸分解制御剤を含有する、ヒアルロン酸による組織修復の補正のための局所投与用製剤。
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