JP5087011B2 - 眼疾患モデル用非ヒト動物 - Google Patents
眼疾患モデル用非ヒト動物 Download PDFInfo
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- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
- A01K67/00—Rearing or breeding animals, not otherwise provided for; New or modified breeds of animals
- A01K67/027—New or modified breeds of vertebrates
- A01K67/0275—Genetically modified vertebrates, e.g. transgenic
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
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- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
- C07K14/47—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
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- A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
- A01K2217/00—Genetically modified animals
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- A01K2217/075—Animals genetically altered by homologous recombination inducing loss of function, i.e. knock out
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- A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
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- A—HUMAN NECESSITIES
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Description
以下、非限定的な実施例を示して本発明をさらに詳細に説明する。
ワシントン大学のSwat W.博士の研究室から分与されたVav2ko、米国マサチューセッツ州ハーバード大学のFrederick W.Alt博士の研究室から分与されたVav3koをそれぞれC57BL/6マウスにバッククロスした後、Vav2koとVav3koをかけ合わせてVav2/3koを得た。Vav2ko、Vav3ko及びVav2/3ko各4匹を、北海道大学医学研究科でのSPFレベルでのバリアフリーという条件下で動物委員会の指針に沿い通常に飼育した。Tonolab rebound tonometer(フィンランド、Tiolat社製)を用い、マニュアルに推奨された条件下で午前10時から12時の間に眼圧を週齡別に測定した。この実験を別々のマウスを用いて4回繰り返し、各種計16匹について行った。得られたデータをtwo−tailed Student’s t−test検定を用いて解析して標準偏差を算出した(P<0.01)。またコントロールとしてC57BL/6マウスを用意し、眼圧を同時に測定した。この結果を図1(Vav2ko)、図2(Vav3ko)及び図3に(Vav2/3ko)にそれぞれ示す。
また、Vav2/3koでは眼圧の上昇は著しく、6週齢のVav2/3koにおける眼圧は、コントロールマウスに対して約40%上昇していた。
コントロールマウス(B6マウス)22例(表1)、及びVav2/3ko18例(表2)から左右の眼球を取り出し、包埋、薄切の後、ヘマトキシンーエオシン(HE)染色(Sigma)を施した病理組織標本を作製した。標本を光学顕微鏡により検査した。
本発明に係るVav2/3koとそのバックグランドであるC57BL/6野生型(コントロール)の2種類のマウスを実施例1と同条件で3週、10週、15週、30週まで飼育した。各マウスをペントバルビタールナトリウム溶液にて深麻酔した後、眼球を素早く摘出し、前眼房組織の観察用に、10%ホルマリンを含む脱イオン化中和メタノール溶液にて希釈した電顕用2.5%グルタルアルデヒド(TAAB社)にて一方の眼球を固定した。もう一方の眼球は、網膜の観察用に、デビットソン溶液を用いて12時間固定した。固定後の組織をパラフィン包埋し、ミクロトームにて矢状断に5μmの切片とした。その後脱パラフィン化し、脱水処理した後、切片をHE染色した。このHE染色の結果を図13及び図14に示す。
8〜9週齢のVav2/3ko(12例)について、午前10〜12時にTonometerを用いて眼圧を測定した後、緑内障治療薬であるプロスタグランジン誘導体のラタノプラスト(Latanoplast、Cayman Chemical社、0.01%/PBS)3μLを点眼し、3時間後に再び眼圧を測定した。コントロールとしてPBSのみを投与した群を同時に用意し、Student’s t−testで検定を行った(P<0.05)。その結果、Latanoprost投与によるVav2/3koの眼圧の低下が認められた(図15)。すなわち、該マウスが緑内障治療薬の有用な評価モデルとなることが確認された。
7週齢のVav2/3koとVav2ko各20例対して、午前10〜12時にTonometerを用いて眼圧を測定した後、0.02%塩化ベンザルコニウム、0.5%NaH2PO4、0.6%Na2HPO4、0.4%塩化ナトリウム、及び0.005%ラタノプロスト(Cayman Chemical社)を含む溶液3μL、又はラタノプラストを含まない上記組成のコントロール溶液を、盲検定方法にて点眼投与し、3時間後に再び眼圧を測定した。また、Vav2/3koに対しては、ラタノプロストとは眼圧降下作用機序が異なるとされているマレイン酸チモロール点眼液(商品名チモプトール、米メルク社、0.5%溶液)3μL又は塩酸ドルゾラミド点眼液(商品名トルソプト、米メルク社、1%溶液)3μLを、上記ラタノプロストを含む溶液に代えて点眼投与し、点眼から2時間後の眼圧変化を測定した。
10週齢のC57BL/6マウスから眼球を摘出し、隅角線維柱帯(Trabecular Meshwork)、光彩、毛様体、角膜、網膜、レンズをそれぞれ分離回収した。各組織からTRIzol試薬(Invitrogen社)を用いて全RNAを調製し、AMV Reverse Transcriptase(Invitrogen社)を用い、ABi7500リアルタイムPCR装置(アプライドバイオシステム社)の推奨マニュアルに従って、リアルタイムPCRを行った。Vav2及びVav3に対するプローブはApplied Biosystems INC.からTaqman probe(Vav2:Mm00437287、Vav3:Mm00445082)として購入した。またコントロールとして、グリセロアルデヒド3リン酸脱水素酵素(GAPDH、Applied Biosystems INC.の製造番号:4352339E)のTaqman probeを用いた。
この結果、Vav2、Vav3のいずれも各組織において発現していることが確認された(図19)。
下記の塩基配列からなるプローブを化学合成し、[33P]dATPを用いてラベリングした。
7週齢のVav2/3ko、Vav2ko及びVav3ko各20例に対して、午前10〜12時にTonometerを用いて眼圧を測定した後、眼房水の流出路に作用して眼圧降下作用をもつことが報告されている、Rho−associatedプロテインカイネース阻害剤であるY−27632(カルビオケム社)の1mM/PBS溶液3μL又はPBS溶液3μLを点眼し、投与1時間後に再び眼圧を測定した。その結果、図21で示すように、Vav2/3ko、Vav2ko及びVav3koのいずれに対しても、Y−27632は眼圧降下作用を示さなかった。
Claims (6)
- Vav2遺伝子及び/又はVav3遺伝子の機能を欠損させた非ヒト動物に化合物を投与する工程、及び該化合物の眼疾患に対する治療作用を確認する工程を含む、眼疾患治療作用を有する化合物のスクリーニング方法。
- 非ヒト動物がVav2遺伝子及びVav3遺伝子の機能を欠損させた非ヒト動物である、請求項1に記載のスクリーニング方法。
- 眼疾患が網膜変性を伴う疾患であり、眼圧を測定することで化合物の治療作用を確認する、請求項1又は2に記載のスクリーニング方法。
- 眼疾患が網膜変性を伴う疾患であり、眼組織の病理学的検査によって化合物の治療作用を確認する、請求項1又は2に記載のスクリーニング方法。
- 眼疾患が緑内障である、請求項1〜4の何れかに記載のスクリーニング方法。
- 眼疾患が網膜症、黄斑変性症、又は黄斑浮腫である、請求項1〜4の何れかに記載のスクリーニング方法。
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KR20190132069A (ko) | 2018-05-18 | 2019-11-27 | 울산대학교 산학협력단 | Pde6b 유전자가 결손된 망막 변성 동물 모델 및 이의 제조 방법 |
KR20200093394A (ko) * | 2019-01-28 | 2020-08-05 | 경북대학교 산학협력단 | 안압이 상승된 동물 모델, 그의 제조방법 및 그를 이용한 녹내장 치료제의 스크리닝 방법 |
KR102234258B1 (ko) * | 2019-01-28 | 2021-03-31 | 경북대학교 산학협력단 | 안압이 상승된 동물 모델, 그의 제조방법 및 그를 이용한 녹내장 치료제의 스크리닝 방법 |
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