JP5877862B2 - Dao1−/−マウスを活用したD−アミノ酸関連疾患の評価・スクリーニング方法 - Google Patents
Dao1−/−マウスを活用したD−アミノ酸関連疾患の評価・スクリーニング方法 Download PDFInfo
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Description
Dao1G181Rは、配列番号3に列挙するDao1遺伝子のcDNAのヌクレオチド配列のうち第661番目のグアニンがアデニンに置換される突然変異である。そのため、野生型では制限酵素HpaIIの切断配列(C↓CGG)になるのに対し、Dao1G181R突然変異体ではCCAGとなり切断されない。ここで突然変異部位を含む第625−726番目のヌクレオチドは第7エクソンに含まれるから(GenBankエントリー番号NM_010018.2)、染色体DNAでもHpaII切断部位の有無によって野生型か突然変異型かを識別することができる。
プロリン及び4−ヒドロキシプロリンは皮膚コラーゲンに多く含まれる。そこでプロリン及び4−ヒドロキシプロリンの両方について同時に全ての光学異性体を分離して定量的に分析することができる方法を開発した。
Swiss Webster Sarcoma 180株の肉腫細胞は10%ウシ胎児血清(Irvine Scientific、ロット#300A80601)添加DMEM(Sigma)培地を用いて5%CO2、37°Cの加湿条件下で培養した。1x107個/mLの懸濁液を調製し、Dao1酵素欠損マウス又は野生型マウスの右後肢フットパットの0.05mLずつ皮内注射により移植した。移植後1週間ごとに腫瘍の長径、短径及び厚みをノギスで計測し、以下の式により腫瘍体積を算出した。
腫瘍体積(mm3)=長径(mm)x短径(mm)x(厚み(mm)−3)
ここで厚みはもともとの足の厚みを3mmとしてその差を腫瘍の厚みとした。
Claims (13)
- (1)Dao1+/+の遺伝子型を有するマウスと、Dao1−/−の遺伝子型を有するマウスとを用意するステップと、
(2)前記Dao1+/+の遺伝子型を有するマウスと、前記Dao1−/−の遺伝子型を有するマウスとの生体組織に腫瘍を移植するステップと、
(3)前記Dao1+/+の遺伝子型を有するマウスと、前記Dao1−/−の遺伝子型を有するマウスとの生体組織に腫瘍を移植したことによる影響を分析するステップとを含む、マウスの生体組織に対する腫瘍移植による、病理的特性、癌及び/又は細胞増殖の亢進及び/又は抑制に関連する特性、D-アミノ酸含有量の変動からなる群から選ばれる1以上の影響の評価方法。 - 前記ステップ(1)は、Dao1+/+、+/−及び/又は−/−の遺伝子型のマウスを個体識別するステップと、前記個体識別されたマウス個体のそれぞれから染色体DNAを抽出するステップと、前記抽出された染色体DNAのうちDao1遺伝子の第7エクソンを含む領域を増幅して増幅DNA断片を得るステップと、前記増幅DNA断片をHpaII制限酵素で消化するステップと、前記増幅DNA断片の制限酵素消化産物を分析するステップとを含む、Dao1+/+、+/−及び/又は−/−遺伝子型の判定方法によって、前記Dao1+/+の遺伝子型を有するマウスと、前記Dao1−/−の遺伝子型を有するマウスとを選別することを含むことを特徴とする、請求項1に記載の評価方法。
- 前記増幅DNA断片を得るステップは、配列番号1及び2に列挙されるヌクレオチド配列からなるオリゴヌクレオチドプライマーを用いて増幅することを含むことを特徴とする、請求項2に記載の評価方法。
- 前記Dao1+/+の遺伝子型を有するマウスと、Dao1−/−の遺伝子型を有するマウスとは、他の遺伝子のうち少なくとも1個について対立遺伝子の組合せが同一であることを特徴とする、請求項1ないし3のいずれか1つに記載の評価方法。
- 前記他の遺伝子の対立遺伝子の組合せはHr−/−を含むことを特徴とする、請求項4に記載の評価方法。
- 前記ステップ(3)は、前記ステップ(2)の前に、前記Dao1+/+の遺伝子型を有するマウスと、前記Dao1−/−の遺伝子型を有するマウスとの生体組織中のD−アミノ酸含有量を測定すること、前記ステップ(2)の後に、前記試験条件に曝露した後で、前記Dao1+/+の遺伝子型を有するマウスと、前記Dao1−/−の遺伝子型を有するマウスとの生体組織中のD−アミノ酸含有量を測定すること、及び、前記ステップ(2)の前に測定されたD−アミノ酸含有量と、前記ステップ(2)の後に測定されたD−アミノ酸含有量とを比較することを含む、請求項1ないし5のいずれかに記載の評価方法。
- 前記D−アミノ酸含有量は、光学分割カラム系を用いるカラムクロマトグラフィーによって測定されることを特徴とする、請求項6に記載の評価方法。
- 前記D−アミノ酸含有量は、光学異性体を識別するモノクローナル抗体を用いる免疫学的手法によって測定されることを特徴とする、請求項6に記載の評価方法。
- 前記D−アミノ酸はD−プロリンであることを特徴とする、請求項6ないし8のいずれかに記載の評価方法。
- 前記D−アミノ酸含有量を測定する生体組織は、真皮、表皮、腎臓、膵臓、精巣、副腎、小脳、下垂体及び血清からなるグループから選択される1種または2種以上の生体組織であることを特徴とする、請求項6ないし9のいずれかに記載の評価方法。
- 前記D−アミノ酸はD−プロリンであり、該D−プロリンは光学分割カラムを用いるカラムクロマトグラフィーによって測定され、前記生体組織は真皮又は表皮であることを特徴とする、請求項10に記載の評価方法。
- Dao1+/+及びHr−/−の遺伝子型を有するマウスと、Dao1−/−及びHr−/−の遺伝子型を有するマウスと、配列番号1及び2に列挙するヌクレオチド配列からなるオリゴヌクレオチドプライマーと、プロリンの光学異性体を識別する光学分割カラム系と、腫瘍細胞とを含むことを特徴とする、請求項11に記載の評価方法を実施するための評価システム。
- 医薬品の候補物質を投与後において、請求項12に記載の評価システムによって、マウスの生体組織に対する腫瘍移植による病理的特性、癌及び/又は細胞増殖の亢進及び/又は抑制に関連する特性、D−アミノ酸含有量の変動からなる群から選ばれる1以上の影響を評価することによる、医薬品の候補物質のスクリーニング方法。
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