JP5866332B2 - 感光性イオンを通過させる分子 - Google Patents
感光性イオンを通過させる分子 Download PDFInfo
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- JP5866332B2 JP5866332B2 JP2013500217A JP2013500217A JP5866332B2 JP 5866332 B2 JP5866332 B2 JP 5866332B2 JP 2013500217 A JP2013500217 A JP 2013500217A JP 2013500217 A JP2013500217 A JP 2013500217A JP 5866332 B2 JP5866332 B2 JP 5866332B2
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- C12N2800/107—Plasmid DNA for vertebrates for mammalian
Description
いくつかの実施形態において、光は、約580〜630nmの波長を有する。いくつかの実施形態において、光は、約589nmの波長を有する。いくつかの実施形態において、光は、約630nmを超える波長(例えば、740nm未満)を有する。いくつかの実施形態において、光は、約630nmの波長を有する。いくつかの実施形態において、光活性化タンパク質は、配列番号3に示される配列と少なくとも95%同一であるアミノ酸配列を含む。いくつかの実施形態において、光活性化タンパク質は、配列番号3に示される配列と少なくとも90%、91%、92%、93%、94%、95%、96%、97%、98%、99%、または100%同一であるアミノ酸配列を含む。いくつかの実施形態において、光活性化タンパク質は、細胞の原形質膜の偏光状態を調節するために、光に対する感受性を増加もしくは減少させる、光の特定の波長に対する感受性を増加もしくは減少させる、および/または光活性化タンパク質の能力を増加もしくは減少させるような、天然アミノ酸配列に導入された置換、欠失、および/もしくは挿入を含む。いくつかの実施形態において、光活性化タンパク質は、1つ以上の保存的アミノ酸置換を含む。いくつかの実施形態において、光活性化タンパク質は、1つ以上の非保存的アミノ酸置換を含む。天然アミノ酸配列に導入される置換、欠失、および/もしくは挿入を含む光活性化タンパク質は、適切に、光に応答して神経細胞の原形質膜を過分極化する能力を保する。
本発明の一実施形態において、生物学的部分204は、光感受性であるように修飾されている標的細胞202からなり得る。本発明の別の実施形態において、生物学的部分204は、標的細胞202を光に対して感受性にさせる、遺伝子導入ベクター等の生物学的素子を含有してもよい。この一例は、DChR発現のための遺伝子を担持するレンチウイルスである。このようにして、標的細胞202の刺激を、埋め込み型装置により制御することができる。例えば、制御回路208を、光源206の作動もしくは非作動、または光源206に電力を供給するバッテリーの充電により、外部信号に応答するように構成することができる。一例では、この外部信号は、制御回路208により受け取られる電磁放射線である。例えば、無線周波数(RF)信号は、外部RF送信機により伝達されて、制御回路208により受け取られ得る。別例では、磁場を用いて、制御回路を作動させる、および/または電力を供給することができる。
DChRまたはGtR3を介した青色光に対する感受性は、ウイルスベクターが、前述の正常細胞に応答する遺伝子を挿入するとき、誘発されるため、挿入は、特定の細胞のサブタイプにより発現される生成物に遺伝的に標的され得る。例えば、ドーパミン作動性ニューロンにのみ生じ、青色光に反応するコリン作動性ニューロンには生じないことは有利であり得る。
Warren Pear.Transient Transfection Methods for Preparation of High−Titer Retroviral Supernatants,Supplement 68.Current Protocols in Molecular Biology,9.11.1−9.11.18.John Wiley & Sons,Inc.(1996).
R.E.Kingston.C.A.Chen.H.Okayama,and J.K.Rose.Transfection of DNA into Eukarotic Cells.Supplement 63.Current Protocols in Molecular Biology,9.1.1−9.1.11,John Wiley & Sons,Inc.(1996)
R.Mortensen.J.D.Chesnut.J.P.Hoeffler.and R.E.Kingston.Selection of Transfected Mammalian Cells,Supplement 62.Current Protocols in Molecular Biology,9.5.1−09.5.19.John Wiley & Sons,Inc.(1997).
H.Potter.Transfection by Electroporation,Supplement 62.Current Protocols in Molecular Biology,9.3.1−9.3.6.John Wiley & Sons,Inc.(1996).
T.Gulick.Transfection using DEAE−Dextran,Supplement 40.Current Protocols in Molecular Biology,9.2.1−9.2.10.John Wiley & Sons,Inc.(1997).
R.E.Kingston.C.A.Chen.H.Okayama.Transfection and Expression of Cloned DNA,Supplement 31.Current Protocols in Immunology (CPI),10.13.1−10.13.9.John Wiley & Sons,Inc.
上の参照文献のそれぞれは、参照によりその全体が組み込まれる。
この図では、ウェルプレート2401(ウェル2405を含有する「トレイ」としても本明細書に称される(例)は、番号1〜12で表示される列2425と、文字A〜Hで表示される行2420で構成される。より具体的には、一例示的な列および行は、それぞれ、2410および2415で定義される。
あるいは、複数の光源は、所望の組み合わせにおいて光応答性タンパク質の刺激を可能にするが、他のタンパク質を刺激しないまま残すように使用することができる。
逆に、過剰な内分泌物および外分泌物を作り出される症候群は、光遺伝学的安定化を用いて治療することができる。便秘(特に、脊髄損傷のある患者の便秘)から巨大結腸症にまで及ぶ、腸運動低下障害は、腸内の運動ニューロンの光遺伝学的興奮により治療することができる。いくつかの形態の過敏性腸症候群を含む腸運動過剰障害は、運動を制御するニューロンの光遺伝学的安定化により治療してもよい。神経原性の胃流出路閉塞は、胃の幽門部におけるニューロンおよび筋組織の光遺伝学的安定化により治療することができる。運動性低下症候群(hypomobility syndrome)に対する1つの代替的アプローチは、腸壁中の伸張感受性ニューロン(stretch−sensitive neuron)に対して光遺伝学的興奮を与え、それにより、その腸がいっぱいになっており、排出(emptying)を必要としているという信号を増加させることである。
図30Aの右下部分は、約50%のピーク回復(P2−S1)/(P1−S1)を示す、パルス20秒間隔の要約プロットを示す。20秒後、ピークは、(45.2±6.6)%まで回復する。図30Bは、長期間の連続光曝露に対するNpHR3.0の正規化した光電流の時間経過を示す(n=11;種々のプロット化は、平均値±SEMである)。図30Cは、10分間にわたるeNpHR3.0の安定性の外向き電流を示す(593nmの光送達は、実線の棒で示される、出力密度:2.5mW/mm2)。
実験手順
構築体
一次培養海馬ニューロンを、P0 Spague−Dawley仔ラットから調製した。CA1およびCA3領域を単離し、0.4mg/mLのパパイン(Worthington,Lakewood,NJ)で消化され、65,000/cm2の密度で、1:30のマトリゲル(Beckton Dickinson Labware,Bedford,MA)でプレコートされたガラス製のカバースリップ上に播種した。カバースリップ上に成長させた海馬培養物に、トランスフェクトされたか、または全ての構築体に対してタイターが一致したウイルスを、4日間インビトロで(DIV)形質導入した(ニューロン成長培地中の最終希釈104感染単位(i.u.)/mL)。前に記述されたように、ホールセルパッチクランプ記録法を行った(Zhang et al.,2007b)。一次海馬培養は、タイターで一致させたウイルスを用いて、4日間インビトロで感染させた(ニューロン成長培地中の最終希釈104感染単位/mL)。14日間インビトロで、培養は、氷冷した4% パラホルムアルデヒドで30分間固定し、次いで、2%正常ロバ血清(NDS)中の0.4% サポニンで30分間透過させた。一次抗体インキュベーションは、4℃で一晩行い、Cy3共役型二次抗体(Jackson Laboratories,West Grove,PA)を、室温で1時間2% NDS中に適用した。画像は、63倍/1.4 NA油浸対照を用いてLeica共焦点顕微鏡上で得た。
成体マウスおよびLong−Evansラットを、Stanfordでの承認されたプロトコルに従って収容した。全ての手術は、無菌状態下で行われた。動物を、ケタミン(80mg/kg)/キシラジン(15〜20mg/kg)のカクテル(Sigma)の腹腔内注射で麻酔した。ウイルスを10μLの注射器および細い34ゲージの金属針を介して送達し、注射容量および流量(0.1μL/分で1μL)を、World Precision Instruments(Sarasota,FL)からの注入ポンプで制御した。オプシンの機能性の検証のために、生きた齧歯動物における同時の光学的な刺激および電気的記録を、記録されたニューロンの照射を確実にするために、光ファイバーの先端よりも深い(約0.4mm)電極の先端を用いて、光ファイバー(約200μm)に結合された細胞外タングステン電極(1MΩ、約125μm)からなるオプトロードを用いて、以前に記述されたように行った(Gradinaru et al.,2007)。光ファイバーは、CrystaLaserからの473nm(ChR2用)または560nm(eNpHR3.0用)レーザーダイオード(10mWのファイバー出力)に連結した。オプトロード記録は、1.5% イソフルランで麻酔した齧歯動物において行い、オプトロードは、標的領域上に形成された小開頭して設置した。データの収集およびファイバーを介した光パルスの生成の両方にpClamp 10およびDigidata 1322Aボードを用いた。記録された信号を、300Hz低/5kHz高でバンドパスフィルターに通した(1800微小電極 AC増幅器)。
脳切片の調製のために、マウスまたはラットを、ウイルスを注射してから4〜5週間後に殺処分した。齧歯動物は、20mLの氷冷したPBS、続いて、20mLの4% パラホルムアルデヒドで灌流した。次いで、脳を4% パラホルムアルデヒド中で一晩固定し、30% スクロース溶液に2日間移した。脳を冷凍し、冠状切片(40μm)を、Leica SM2000Rクリオスタットで調製し、抗凍結剤(PBS中の25% グリセロールおよび30% エチレングリコール)中で、4℃で保存した。切片(DAPI染色 1:50,000)を、顕微鏡用スライド上にPVA−DABCOで装着し、単一の共焦点光学的断面(例えば、背部のCA1領域を通して、ブレグマよりも約1〜2.5mm後方、または背側鉤状回、ブレグマよりも2.7〜3mm後方)を、Leica共焦点顕微鏡上に、10倍の空気および40倍/1.4 NA油浸対照を用いて得た。
オプシン源
本明細書に記載の全てのオプシンは、ヒトコドン使用分布に従うようにそれぞれの遺伝子のコドンを変化させることにより、哺乳動物発現に対して最適化されている(http://www.kazusa.or.jp/codon/cgi−bin/showcodon.cgi?species=9606)。本来のAR、BR、およびGtR3配列についてのGenBank受入コードは、DQ074124、M11720、およびEG722553である。
全てのNpHR変異体は、既刊のNpHR−EYFP構築体のPCR増幅により生成し(Zhang et al.,2007b)、標準的な分子生物学プロトコルに従って、CaMKIIαまたはシナプシン−1プロモータを運搬するレンチウイルスのAgelおよびEcoRI制限酵素認識部位に、インフレームにクローン化した。同様の戦略をBRおよびARのために使用した。GtR3を、ゲノムサーチを通じて特定した。本明細書に記載の全てのオプシンは、ヒトコドン使用分布に従うようにそれぞれの遺伝子のコドンを変化させることにより、哺乳動物発現に対して最適化されており(http://www.kazusa.or.jp/codon/cgi− bin/showcodon.cgi?species=9606)、最適化された配列は、カスタム合成した(DNA2.0,Inc.,Menlo Park,CA)。本来のAR、BR、およびGtR3配列についてのGenBank受入コードは、DQ074124、M11720、およびEG722553である。pAAV−EF1a−mCherry−IRES−WGA−Cre ベクターを、標準的な分子生物学プロトコルを用いて構築した。WGAおよびCre遺伝子のコドンを、哺乳動物細胞中の発現のために最適化した。遺伝子は、DNA2.0(Menlo Park,CA)により合成した。Creを、WGAのC末端にインフレーム融合させ、これを、同様に、IRESに融合させた。mCherry−IRES−WGA−Creバイシストロニック発現カセットを、EMCV IRES配列を用いて設計した。pAAV−EF1a プラスミドバックボーンは、前に記述されたものと同一である(Sohal et al.,2009、Tsai et al.,2009)。pAAV−hSyn−eNpHR3.0−EFYP−P2A−ChR2H134R−mCherryを、5’末端でER移行配列を有するp2A領域および3’末端でhChR2から始まる20塩基を含有した120−merプライマーで構築した(5’caagttctgctacgagaacgaggtgggctccggagccacgaacttctctctgttaaagcaagcaggagacgtggaagaaaaccccggtcccatggactatggcggcgctttgtctgccg3’)。まず、ChR2(H134R)−mCherryフラグメントを、順方向プライマーとして、120−merおよび逆プライマーとして、5’−atatcgaattctcattacttgtacagctcgt−3’を用いて増幅した。次に、この増幅された生成物を、干渉されたp2A領域を用いてeNpHR 3.0−EYFPをChR2(H134R)−mCherryに融合するために、順方向プライマー5’−ccggatccccgggtaccggtaggccaccatgacagagaccctgcct−3’とともに、逆プライマーとして使用した。次いで、3.4Kbフラグメントを精製し、pAAV−hSynベクターのBamHIおよびEcoRI部位にクローン化された。全ての構築体は、クローニングの精度のために完全に配列化され、最新マップは、http://www.optogenetics.org.のオンラインで入手可能であり、これらの内容は、参照によりそれらの全体が本明細書に組み込まれる。
培養されたニューロン感染およびインビボ注入のためのレンチウイルスを、前に記述されたように生成した(Zhang et al.,2007b)。ウイルス滴定は、24ウェルプレート中で増殖され、ポリブレン(8μg/ml)の存在下で5倍の連続希釈でインキュベートされたHEK293細胞において行われた。4日間後、培養物をPBS中に再懸濁し、(サンプルあたり20,000の症例を回収する)FACScanフローサイトメーター上でEYFP蛍光について分別し、続いて、FlowJoソフトウェア(Ashland,OR)を用いて分析した。ウイルスの滴定度は、以下のように決定した:[(感染した細胞の割合%)×(ウェル中の細胞の総数)×(希釈係数)]/(細胞に付加した接種材料の容量)=感染単位/mL。培養感染のウイルスに対する滴定度は、105感染単位/mLであった。インビボ注入のための濃縮したウイルスの滴定度は、1010感染単位/mLであった。
一次培養海馬ニューロンをP0 Spague−Dawley仔ラットから調製した。CA1およびCA3領域を単離し、0.4mg/mLのパパイン(Worthington,Lakewood,NJ)で消化し、65,000/cm2の密度で、1:30のマトリゲル(Beckton Dickinson Labware,Bedford,MA)でプレコートされたガラス製のカバースリップ上に播種した。培養物は、1.25% FBS(Hyclone,Logan,UT)、4% B−27 supplement(GIBCO,Grand Island,NY)、2mM Glutamax(GIBCO)、およびFUDR(2mg/mL、Sigma,St.Louis,MO)を含有するNeurobasal−A培地(Invitrogen Carlsbad,CA)を用いて5%CO2湿潤インキュベータ内で維持した。
6〜10に分けた海馬ニューロンを、24ウェルプレート中で65,000細胞/ウェルで増殖させた。それぞれのウェルに対してDNA/CaC CI2混合:15μLの総H2O中の1.5〜3μgのDNA(QIAGEN 内毒素のない調製物)+1.875μLの2M CaC CI2(最終Ca2+濃度 250mM)。DNA/CaCl2に、15μLの2X HEPES緩衝食塩水(pH7.05)を添加し、最終容量をピペット操作により十分に混合した。室温で20分間後、30μLのDNA/CaCI22/HBSの混合物を、それぞれのウェルに滴加し(ここから成長培地が一時的に除去され、400μLの温かいMEMと置き換えた)、37℃で45〜60分間、トランスフェクションを開始した。次いで、それぞれのウェルを3×1mLの温かいMEMで洗浄し、成長培地を置き換えた。オプシン発現は、通常、20〜24時間以内に観察された。
カバースリップ上に成長させた海馬培養物に、全ての構築体に対して滴定度が一致したウイルスを、4日間インビトロで形質導入し(神経細胞成長培地中の最終希釈104感染単位/mL)、1週間発現させた。ホールセルパッチクランプ記録を、前に記述されたように行った(細胞内溶液:129mM K−グルコン酸塩、10mM HEPES、10mM KCI、4mM MgATP、0.3mM Na3GTP、pH7.2まで滴定;細胞外タイロード:125mM NaCl、2mM KCI、3mM CaCl2、1mM MgCl2、30mM グルコース、および25mM HEPES、pH7.3まで滴定)。電圧クランプ記録のために、細胞は、−70mVで保たれた。可視範囲内の光を、300W DG−4ランプ(Sutter Instruments,Novato,CA)から異なる波長の選択性のあるフィルター(Semrock,Rochester,NY)およびLeica 40X/0.8NA水浸対物を通じて送達した。パワースペクトルを除くフィルター(波長nm/帯域幅nm/出力mW/mm2として本明細書に示される)は、406/15/3、472/30/18.5、560/14/7、589/15/7.5、593/40/15.5、630/20/3.5であった。遠赤色光および近赤外線の送達:660nmの抑制剤に対する光(7mW/mm2)を、発光ダイオードおよび40×/0.8NA水浸対物を用いて送達した。680nmの抑制剤に対する光(7mW/mm2)を、680±13nmのフィルターを通じて、X−Cite 120Wハロゲン光源および40×/0.8NA水浸対物を用いて送達した。eNPAC、ChR2(H134R)、およびeNpHR3.0のパワースペクトルの光送達は、異なる波長の25mmフィルターのために、10ポジションホイールを有するラムダ10−3フィルターホイール(Sutter Instruments)を装備する300W DG−4ランプおよび40×/0.8NA水浸対物から送達した。フィルター(波長nm/帯域幅nm/出力mW/mm2として本明細書に示される)は、387/10/3.5、406/15/3.5、427/10/4.0、445/20/4.0、470/22/4.0、494/20/4.5、520/15/4.5、542/27/5.0、560/20/5.0、590/20/3.5、630/20/3.5であった。図1、3A〜3D、および4および図S2(下表5を参照のこと)については、共焦点像およびホールセルパッチクランプデータは、レンチウイルスNpHR、BR、GtR3、およびARベースの構築体を用いて、トランスフェクトされるか(共焦点データ)、あるいは変換される(パッチデータ)のいずれかで、1週間発現される、培養された海馬ニューロン由来のものである。発現は、ヒトシナプシンIプロモータにより駆動され、EYFPへの融合により可視化された。
一次海馬培養は、タイターで一致させたウイルスを用いて、4日間インビトロで感染させた(神経細胞成長培地中の最終希釈104感染単位/mL)。14日間インビトロで、培養物を、氷冷した4% パラホルムアルデヒドで30分間固定し、次いで、2%正常ロバ血清(NDS)中の0.4% サポニンで30分間透過した。一次抗体のインキュベーションを、KDEL保留シグナル(KDEL 1:200、Abeam,Cambridge,MA)を含有する内因性小胞体タンパク質を認識する小胞体のモノクローナルマーカーを用いて、4℃で一晩行った。Cy3共役させた二次抗体(Jackson Laboratories,West Grove,PA)を、室温で1時間2% NDS中に適用した。画像は、63倍/1.4NA油浸対照を用いてLeica共焦点顕微鏡上で得た。
成体マウスおよびLong−Evansラットを、Stanfordでの承認されたプロトコルに従って収容した。全ての手術は、無菌状態下で行われた。動物を、ケタミン(80mg/kg)/キシラジン(15〜20mg/kg)のカクテル(Sigma)の腹腔内注射で麻酔した。頭部を定位固定装置(Kopf Instruments,Tujunga,CA;Olympus立体顕微鏡)中に設置した。眼科用の軟膏を眼の乾燥を防ぐために適用した。正中頭皮切開が行われ、小規模の開頭術を定位固定装置(Fine Science Tools,Foster City,CA)上に実装されたドリルを用いて行った。ウイルスを10μLの注射器および細い34ゲージの金属針を用いて送達し、注射容量および流量(0.1μL/分で1μL)を、World Precision Instruments(Sarasota,FL)からの注入ポンプで制御した。注入後、この針をさらに5分間放置し、次いで、徐々に引き抜いた。皮膚をVetbond組織接着剤を用いて元の位置に接着した。この動物は、麻酔から回復するまで、加温パッド上に保持した。ブプレノルフィン(0.03mg/kg)を、不快感を最小限に抑えるために、外科手術後、皮下に投与した。図2Aの実験では、背部CA1の大きな面積を覆うために、CaMKIIαプロモータ下で、eNpHR3.1(N末端シグナルペプチドを有するeNpHR3.0の短い形態、元のNpHRの初めから17個のアミノ酸を除去した)を担持する1μLの濃縮されたレンチウイルス(1010感染単位/mL)を、それぞれの海馬において、2つの部位にマイクロ注入した(部位1:ブレグマから前後−1.5mm;側部、±1mm;腹部、1.5mm;部位2:AP、ブレグマから−2.5mm;側部、±2mm;腹部、1.5mm)。図2Dおよび2Eでは、2つの異なるアデノ随伴ウイルス(AAV)(ウイルス滴定度2×1012g.c./mL)を、同じ手術中、0.15uL/分の注入速度を用いて、定位的に注入した。高い滴定度(2×1012g.c./mL)AAVを、UNC VectorCoreにより生成した。図2Dでは、eNpHR3.0−EYFP(AAV5−Efla−DIO−eNpHR3.0−EYFP)を担持する二重に惹起されたcre依存性AAV5を、M1に注入し、AAV2−Eflα−mCherry−IRESWGA−Creを成体Long−EvansラットのS1に注入した。1μLのウイルスを、以下の調整物により定義された5つの異なる部位で送達した:M1の注入I:AP、ブレグマから+1mm;側部、1.5mm;腹部、2mm;M1の注入II:AP、+2mm;側部、1.5mm;腹部、2mm;S1の注入I:AP、−0.3mm;側部、3.4mm;腹部、2mm;S1の注入II:AP、−1.3mm;側部、3mm;腹部、2mm;S1の注入III:AP、−2.12mm;側部、3mm;腹部、2mm。図2Eでは、1μLのウイルスを、成体BL6マウスの歯状回(DG)に左右対称に注入した。AAV8−EF1a−DIO−ChR2−EYFPを、以下の調整物を用いて、右側DGに注入し、AAV2−EF1a−mCherry−IRES−WGA−Creを、左側DGに注入した:AP、ブレグマから−2.1;側部、±1.05mm;腹部、2.1mm。
WGA−Creシステムにおいてオプシン機能性を検証するために、生きている齧歯動物における同時の光学的な刺激および電気的記録を、記録されたニューロンの照射を確実にするために、光ファイバーの先端よりも深い(約0.4mm)電極の先端を有する光ファイバー(約200μm)に結合された細胞外タングステン電極(1MΩ、約125μm)からなるオプトロードを用いて、前に記述されたように行った(Gradinaru et al.,2007)。光ファイバーは、CrystaLaserからの473nm(ChR2用)または560nm(eNpHR3.0用)レーザーダイオード(10mWのファイバー出力)に連結した。オプトロード記録は、1.5% イソフルランで麻酔した齧歯動物において行い、オプトロードは、標的領域上に形成された開頭術を通して設置した。pClamp10およびDigidata1322Aボードは、データを回収することと、光ファイバーを通じて光パルスを発生させることの両方のために用いた。記録された信号を、300Hz低/5kHz高でバンドパスフィルターに通した(1800微小電極 AC増幅器)。光ファイバー/電極対の精密な設置のために、定位固定用の器具類を用いた。
脳切片の調製のために、マウスまたはラットを、ウイルスを注射してから4〜5週間後に殺処分した。齧歯動物は、20mLの氷冷したPBS、続いて、20mLの4% パラホルムアルデヒドで灌流した。次いで、脳を4% パラホルムアルデヒド中で一晩固定し、30% スクロース溶液に2日間移した。脳を冷凍し、冠状切片(40μm)を、Leica SM2000Rクリオスタットで調製し、抗凍結剤(PBS中の25% グリセロール、30% エチレングリコール)中で、4℃で保存した。切片(DAPI染色 1:50,000)を、顕微鏡用スライド上にPVA−DABCOで装着し、単一の共焦点光学的断面(例えば、背部のCA1領域を通して、ブレグマよりも約1〜2.5mm後方、または背側鉤状回、ブレグマよりも2.7〜3mm後方)が、Leica共焦点顕微鏡上で、10倍の空気および40倍/1NA油浸対照を用いて得た。
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Claims (21)
- 細胞膜上に発現される光活性化タンパク質を含む動物細胞であって、前記タンパク質は、
a)配列番号:3、配列番号:1、配列番号:2、または配列番号:4に示される配列と少なくとも95%同一であるコアアミノ酸配列、
b)小胞体(ER)移行シグナル、及び、
c)膜輸送シグナル、を含み、
これらをN末端からC末端にかけて、
i)前記コアアミノ酸配列、前記ER移行シグナル、および前記膜輸送シグナルの順、または
ii)前記コアアミノ酸配列、前記膜輸送シグナル、および前記ER移行シグナルの順で含む、動物細胞。 - 前記膜輸送シグナルは、アミノ酸配列KSRITSEGEYIPLDQIDINVを含む、請求項1に記載の動物細胞。
- 前記ER移行シグナルは、アミノ酸配列FCYENEVを含む、請求項1又は2に記載の動物細胞。
- 前記動物細胞は、神経細胞、筋細胞、または幹細胞である、請求項1から3のいずれか1項に記載の動物細胞。
- 前記細胞がニューロンであり、かつ、前記細胞膜上に発現される第2の光活性化タンパク質をさらに含む、請求項1から4のいずれか1項に記載の動物細胞。
- 前記第2の光活性化タンパク質は、前記細胞が光で照射されるとき、前記細胞中で脱分極電流を媒介することができるタンパク質である、請求項5に記載の動物細胞。
- 前記第2の光活性化タンパク質は、VChR1、ChR2、及びSFOからなる群から選択される、請求項5に記載の動物細胞。
- 請求項1から7のいずれか1項に記載の細胞を含む、細胞集団。
- a)配列番号:3、配列番号:1、配列番号:2、または配列番号:4に示される配列と少なくとも95%同一であるコアアミノ酸配列、
b)小胞体(ER)移行シグナル、及び、
c)膜輸送シグナル、を含み、
これらをN末端からC末端にかけて、
i)前記コアアミノ酸配列、前記ER移行シグナル、および前記膜輸送シグナルの順、または
ii)前記コアアミノ酸配列、前記膜輸送シグナル、および前記ER移行シグナルの順で含む光活性化タンパク質をコードするヌクレオチド配列を含むポリヌクレオチド。 - 前記光活性化タンパク質をコードするヌクレオチド配列は、プロモータに操作可能に連結される、請求項9に記載のポリヌクレオチド。
- 前記プロモータがCaMKIIaプロモータ、またはシナプシンIプロモータである、請求項10に記載のポリヌクレオチド。
- 前記ポリヌクレオチドは、発現ベクター中にある、請求項9に記載のポリヌクレオチド。
- 前記発現ベクターがウイルスベクターである、請求項12に記載のポリヌクレオチド。
- 前記ウイルスベクターは、アデノ随伴ウイルスベクター、レトロウイルスベクター、アデノウイルスベクター、単純ヘルペスウイルスベクター、またはレンチウイルスベクターである、請求項13に記載のポリヌクレオチド。
- 光により前記光活性化タンパク質を活性化することを含む、請求項1から4のいずれか1項に記載の細胞またはその集団の使用方法。
- 前記光活性化タンパク質は、配列番号3に記載のアミノ酸配列と少なくとも95%のアミノ酸配列同一性を有するアミノ酸配列を含み、前記光は580〜630nmの波長を有する、請求項15に記載の方法。
- 前記光活性化タンパク質をそれぞれの波長で活性化することを含む、請求項5から7のいずれか1項に記載の細胞またはその集団の使用方法。
- 請求項1から7のいずれか1項に記載の細胞を含む、非ヒト動物。
- 疾患の治療に使用される、請求項9から14のいずれか一項に記載のポリヌクレオチド。
- a)配列番号:3、配列番号:1、配列番号:2、または配列番号:4に示される配列と少なくとも95%同一であるコアアミノ酸配列、
b)小胞体(ER)移行シグナル、及び、
c)膜輸送シグナル、を含み、
これらをN末端からC末端にかけて、
i)前記コアアミノ酸配列、前記ER移行シグナル、および前記膜輸送シグナルの順、または
ii)前記コアアミノ酸配列、前記膜輸送シグナル、および前記ER移行シグナルの順で含む、光活性化タンパク質。 - 前記ER移行シグナルはアミノ酸配列FCYENEVを含み、及び/又は、前記膜輸送シグナルはアミノ酸配列KSRITSEGEYIPLDQIDINVを含む、請求項20に記載の光活性化タンパク質。
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JP2013524780A (ja) | 2013-06-20 |
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US9604073B2 (en) | 2017-03-28 |
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EP3399024A1 (en) | 2018-11-07 |
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CA2791094A1 (en) | 2011-09-22 |
US20130019325A1 (en) | 2013-01-17 |
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