KR20230082024A - 재프로그래밍을 위한 기능적 단편, 구성 및 이의 응용 - Google Patents
재프로그래밍을 위한 기능적 단편, 구성 및 이의 응용 Download PDFInfo
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Abstract
신경아교세포를 기능적 뉴런 또는 유사한 뉴런으로 전환분화 및 재프로그래밍하기 위해 공동으로 촉진할 수 있는 일련의 전사인자 및 전사인자 조성물을 제공한다. 생체 내 또는 시험관 내에서 일련의 전사 인자의 발현을 촉진함으로써. 신경교세포의 전환분화는 신경계 손상을 복구하는데 효과적으로 사용될 수 있거나 주요 전사 인자의 전환분화 능력은 신경교세포 유래 뇌종양의 악화를 제한하는데 사용된다. 또한, 발견된 전사인자 및 이의 조성물을 신경계 질환 치료제의 제조에 적용하는 것을 제공한다.
Description
본 발명은 생명공학 및 유전자 요법 분야에 속한다. 구체적으로, 본 발명은 신경교세포 유래 세포를 뉴런으로 전환시키는 방법 및 상기 방법을 적용하여 신경계 손상을 복구하거나 신경교세포 유래 종양을 치료하는 방법에 관한 것이다.
포유동물의 중추신경계 손상 및 각종 신경퇴행성 질환으로 인한 주요 병리학적 변화는 신경세포의 돌이킬 수 없는 퇴행 및 괴사 및 신경회로의 파괴이다. 손상되고 병든 뇌나 척수에서 죽고 소실된 뉴런을 어떻게 보충하고 대체하며 신경 회로를 재건하는 것이 치료의 핵심 단계이다. 성체 포유류의 중추신경계(뇌 및 척수)의 자가 복구 능력은 매우 제한적이기 때문에 뉴런 손실을 스스로 보충하기 어렵다.
외인성 신경세포 또는 신경유래세포의 이식 효율이 낮고 종양형성 및 면역원성의 잠재적 위험이 있기 때문에 최근 세포 재프로그래밍 기술의 등장으로 재생의학에 혁명적인 변화를 가져왔고, 단일 또는 다중 전사 인자의 조합의 발현을 통해 생체 내에서 성상세포를 재프로그래밍하여 뉴런을 유도하는 것은 뉴런 대체 요법의 중요한 새로운 전략이 될 것으로 예상된다.
신경교종은 줄여서 신경아교종 (glioma) 이라고 하며, 교모세포종 (glioblastoma) 이라고도 한다. 넓은 의미에서는 신경상피 기원의 모든 종양을 말하고, 좁은 의미에서는 각종 신경아교세포의 종양을 말한다. 신경아교종은 가장 치명적인 악성 종양 중 하나이며 가장 흔한 원발성 중추신경계 종양입니다. 뇌 및 중추신경계 종양의 30%, 뇌 악성 뇌종양의 80%를 차지한다. 그것은 인간의 건강에 심각한 위협입니다. 1999년 세계보건기구(WHO)의 분류체계에 따르면 신경아교종은 성상세포종, 핍지교종, 상의세포종, 혼합형 신경교종, 맥락총종양, 기원 불확실한 신경상피조직종, 혼합형 신경아교세포종양, 송과체실질종양, 배아종양으로 구분된다. 종양 및 신경모세포종 종양. 신경아교종과 정상 신경조직은 경계가 불분명한 십자형으로 자란다.
종양 조직은 청소가 쉽지 않고 재발하기 쉽다. 동시에, 혈액-뇌 장벽의 존재로 인해 일반적인 항종양 약물은 효능이 좋지 않다. 현재, 신경아교종의 치료는 아직 의학계의 임상적 요구를 충족시키지 못했다. 최근 몇 년 동안, 일부 연구에서는 일부 신경 유래 전사 인자 또는 전사 인자의 조합이 신경아교종 세포를 시험관내 또는 생체내에서 신경세포 유사 세포로 변형시킬 수 있고, 신경아교종 세포의 증식을 제한할 수 있다는 것을 발견했다. 그러나 기존의 전사인자 또는 전사인자의 조합은 in vitro 또는 in vivo에서 전환 효율이 낮은 것으로 증명되었을 뿐 실제 임상 적용이 어려운 실정이다.
따라서, 생체 내에서 신경아교세포가 활성 뉴런으로 분화되도록 유도하는 적합한 전사 인자 또는 이들의 조합을 찾는 것은 뇌 및 척수 신경계의 복구에 매우 중요하다. 동시에 전사인자의 리프로그래밍 기술을 참조하여 신경아교세포 유래 신경교종에 적용하는 것도 현시점에서 시급히 해결해야 할 치료계획이다.
본 발명은 신경아교세포의 전환분화를 상승적으로 촉진하고 기능적 뉴런 또는 뉴런-유사 세포로 재프로그래밍하는 전사 인자 및 전사 인자 조합의 그룹을 제공한다. 본 발명은 또한 생체내 또는 시험관내에서 이 전사 인자 그룹의 발현을 증가시키는 방법 및 신경계 질환용 약물의 제조에 이 전사 인자 그룹을 적용하는 방법을 제공한다.
본 발명의 제1 측면은 신경아교세포의 전환분화를 상승적으로 촉진할 수 있는 기능성 단편 세트를 제공하고,
여기서 기능적 단편은 NeuroD1, Brn2, Ascl1, Ngn2, Gsx1, Tbr1, Dlx2, Ptf1a, Pax6 및/또는 Otx2 와 같은 전사 인자의 발현을 촉진하는 것으로부터 선택되는 전사 인자의 발현을 촉진하는 적어도 하나의 기능성 단편을 함유한다.
또 다른 바람직한 예에서, 전환분화는 신경아교세포의 기능성 뉴런으로의 전환분화 또는 재프로그래밍을 의미한다.
다른 바람직한 예에서, 전사 인자의 발현을 촉진하는 기능적 단편은 적어도 Ascl1 전사 인자의 발현을 촉진하는 기능적 단편을 포함한다.
또 다른 바람직한 예에서, Ascl1은 강화된 Ascl1이고, 그의 아미노산 서열은 SEQ ID No: 41에 제시된다.
다른 바람직한 예에서, 전사 인자의 발현을 촉진하는 기능적 단편은 적어도 NeuroD1 전사 인자의 발현을 촉진하는 기능적 단편을 포함한다.
다른 바람직한 예에서, 전사 인자의 발현을 촉진하는 기능적 단편은 적어도 Brn2 전사 인자의 발현을 촉진하는 기능적 단편을 포함한다.
다른 바람직한 예에서, 전사 인자의 발현을 촉진하는 기능적 단편은 적어도 Ngn2 전사 인자의 발현을 촉진하는 기능적 단편을 포함한다.
다른 바람직한 예에서, 전사 인자의 발현을 촉진하는 기능적 단편은 적어도 Gsx1 전사 인자의 발현을 촉진하는 기능적 단편을 포함한다.
다른 바람직한 예에서, 전사 인자의 발현을 촉진하는 기능적 단편은 적어도 Tbr1 전사 인자의 발현을 촉진하는 기능적 단편을 포함한다.
다른 바람직한 예에서, 전사 인자의 발현을 촉진하는 기능적 단편은 적어도 Dlx2 전사 인자의 발현을 촉진하는 기능적 단편을 포함한다.
다른 바람직한 예에서, 전사 인자의 발현을 촉진하는 기능적 단편은 적어도 Ptf1a 전사 인자의 발현을 촉진하는 기능적 단편을 포함한다.
다른 바람직한 예에서, 전사 인자의 발현을 촉진하는 기능적 단편은 적어도 Pax6 전사 인자의 발현을 촉진하는 기능적 단편을 포함한다.
다른 바람직한 예에서, 전사 인자의 발현을 촉진하는 기능적 단편은 적어도 Otx2 전사 인자의 발현을 촉진하는 기능적 단편을 포함한다.
또 다른 바람직한 예에서, 기능적 단편 조합은 NeuroD1, Brn2, Ascl1, Ngn2, Gsx1, Tbr1, Dlx2, Ptf1a, Pax6 및/또는 Otx2와 같은 전사 인자의 발현을 촉진하는 기능적 단편으로부터 선택된 전사 인자의 발현을 촉진하는 적어도 2개의 기능적 단편을 함유한다.
다른 바람직한 예에서, 전사 인자의 발현을 촉진하는 기능성 단편은 적어도 Brn2 전사 인자의 발현을 촉진하는 기능성 단편 및 전사 인자의 발현을 촉진하는 또 다른 기능성 단편을 포함한다. 전사 인자의 발현을 촉진하는 상기 다른 기능성 단편은 NeuroD1, Ascl1, Ngn2, Gsx1, Tbr1, Dlx2, Ptf1a, Pax6 또는 Otx2 및 기타 전사 인자의 발현을 촉진하는 임의의 기능성 단편; 보다 바람직하게는, 전사 인자의 발현을 촉진하는 상기 다른 기능성 단편은 NeuroD1, Ascl1 또는 Ngn2와 같은 전사 인자의 발현을 촉진하는 임의의 기능성 단편으로부터 선택된다.
다른 바람직한 예에서, 전사 인자의 발현을 촉진하는 기능적 단편은 적어도 NeuroD1 전사 인자의 발현을 촉진하는 기능적 단편 및 다른 전사 인자의 발현을 촉진하는 기능적 단편을 포함한다. 전사 인자의 발현을 촉진하는 상기 다른 기능성 단편은 Brn2, Ascl1, Ngn2, Gsx1, Tbr1, Dlx2, Ptf1a, Pax6 또는 Otx2 및 기타 전사 인자의 발현을 촉진하는 임의의 기능성 단편; 보다 바람직하게는, 전사 인자의 발현을 촉진하는 상기 다른 기능성 단편은 Brn2, Ascl1 또는 Ngn2와 같은 전사 인자의 발현을 촉진하는 임의의 기능성 단편으로부터 선택된다.
다른 바람직한 예에서, 전사 인자의 발현을 촉진하는 기능적 단편은 적어도 Gsx1 전사 인자의 발현을 촉진하는 기능적 단편 및 다른 전사 인자의 발현을 촉진하는 기능적 단편을 포함한다. 전사 인자의 발현을 촉진하는 상기 다른 기능성 단편은 NeuroD1, Ascl1, Ngn2, Brn2, Tbr1, Dlx2, Ptf1a, Pax6 또는 Otx2 및 기타 전사 인자의 발현을 촉진하는 임의의 기능성 단편; 보다 바람직하게는, 전사 인자의 발현을 촉진하는 상기 다른 기능성 단편은 Ascl1, Ngn2 또는 Tbr1과 같은 전사 인자의 발현을 촉진하는 임의의 기능성 단편으로부터 선택된다.
또 다른 바람직한 예에서, 전사 인자의 발현을 촉진하는 기능적 단편은 적어도 Tbr1 전사 인자의 발현을 촉진하는 기능적 단편 및 전사 인자의 발현을 촉진하는 다른 기능적 단편을 포함한다. 전사 인자의 발현을 촉진하는 상기 다른 기능성 단편은 NeuroD1, Ascl1, Ngn2, Brn2, Gsx1, Dlx2, Ptf1a, Pax6 또는 Otx2 및 기타 전사 인자의 발현을 촉진하는 임의의 기능성 단편; 보다 바람직하게는, 전사 인자의 발현을 촉진하는 상기 다른 기능성 단편은 Ascl1, Ngn2 또는 Gsx1과 같은 전사 인자의 발현을 촉진하는 임의의 기능성 단편으로부터 선택된다.
다른 바람직한 예에서, 전사 인자의 발현을 촉진하는 기능성 단편은 적어도 Dlx2 전사 인자의 발현을 촉진하는 기능성 단편 및 전사 인자의 발현을 촉진하는 또 다른 기능성 단편을 포함한다. 전사 인자의 발현을 촉진하는 상기 다른 기능성 단편은 NeuroD1, Ascl1, Ngn2, Brn2, Tbr1, Gsx1, Ptf1a, Pax6 또는 Otx2 및 기타 전사 인자의 발현을 촉진하는 임의의 기능성 단편; 보다 바람직하게는, 전사 인자의 발현을 촉진하는 상기 다른 기능성 단편은 Ascl1, Ngn2 또는 Ptf1a와 같은 전사 인자의 발현을 촉진하는 임의의 기능성 단편으로부터 선택된다.
다른 바람직한 예에서, 전사 인자의 발현을 촉진하는 기능적 단편은 적어도 Ptf1a 전사 인자의 발현을 촉진하는 기능적 단편 및 전사 인자의 발현을 촉진하는 다른 기능적 단편을 포함한다. 전사 인자의 발현을 촉진하는 상기 다른 기능성 단편은 NeuroD1, Ascl1, Ngn2, Brn2, Tbr1, Gsx1, Dlx2, Pax6 또는 Otx2 및 기타 전사 인자의 발현을 촉진하는 임의의 기능성 단편; 보다 바람직하게는, 전사 인자의 발현을 촉진하는 상기 다른 기능성 단편은 Ascl1, Ngn2 또는 Dlx2와 같은 전사 인자의 발현을 촉진하는 임의의 기능성 단편으로부터 선택된다.
다른 바람직한 예에서, 전사 인자의 발현을 촉진하는 기능적 단편은 적어도 Pax6 전사 인자의 발현을 촉진하는 기능적 단편 및 전사 인자의 발현을 촉진하는 다른 기능적 단편을 포함한다. 전사 인자의 발현을 촉진하는 상기 다른 기능성 단편은 NeuroD1, Ascl1, Ngn2, Brn2, Tbr1, Gsx1, Ptf1a, Dlx2 또는 Otx2 및 기타 전사 인자의 발현을 촉진하는 임의의 기능성 단편; 보다 바람직하게는, 전사 인자의 발현을 촉진하는 상기 다른 기능성 단편은 Ascl1, Ngn2 또는 Otx2와 같은 전사 인자의 발현을 촉진하는 임의의 기능성 단편으로부터 선택된다.
다른 바람직한 예에서, 전사 인자의 발현을 촉진하는 기능적 단편은 적어도 Otx2 전사 인자의 발현을 촉진하는 기능적 단편 및 전사 인자의 발현을 촉진하는 다른 기능적 단편을 포함한다. 전사 인자의 발현을 촉진하는 상기 다른 기능성 단편은 NeuroD1, Ascl1, Ngn2, Brn2, Tbr1, Gsx1, Ptf1a, Dlx2 또는 Pax6 및 기타 전사 인자의 발현을 촉진하는 임의의 기능성 단편; 보다 바람직하게는, 전사 인자의 발현을 촉진하는 상기 다른 기능성 단편은 Ascl1, Ngn2 또는 Pax6과 같은 전사 인자의 발현을 촉진하는 임의의 기능성 단편으로부터 선택된다.
다른 바람직한 예에서, 전사 인자의 발현을 촉진하는 기능성 단편은 적어도 Ascl1 또는 Ngn2의 임의의 전사 인자의 발현을 촉진하는 기능성 단편 및 NeuroD1, Brn2, Gsx1, Tbr1, Dlx2, Ptf1a, Pax6 또는 Otx2와 같은 전사 인자의 발현을 촉진하는 임의의 기능성 단편으로부터 선택되는 전사 인자의 발현을 촉진하는 다른 기능성 단편을 포함한다.
또 다른 바람직한 예에서, 신경아교세포의 전환분화를 상승적으로 촉진할 수 있는 기능성 단편은 적어도 다음을 포함한다.
두 전사 인자 NeuroD1 및 Brn2의 발현을 촉진하는 기능적 단편,
또는 2개의 전사 인자 Gsx1 및 Tbr1의 발현을 촉진하는 기능적 단편,
또는 2개의 전사 인자 Dlx2 및 Ptf1a의 발현을 촉진하는 기능적 단편,
또는 두 전사 인자 Pax6 및 Otx2의 발현을 촉진하는 기능적 단편.
다른 바람직한 예에서, 신경아교세포의 전환분화를 상승적으로 촉진할 수 있는 기능성 단편은 적어도 Ascl1 또는 Ngn2의 임의의 전사 인자의 발현을 촉진할 수 있는 기능성 단편의 조합 및 신경아교세포의 전환분화를 상승적으로 촉진할 수 있는 또 다른 기능적 단편을 포함한다.
신경아교세포의 전환분화를 상승적으로 촉진할 수 있는 상기 다른 기능성 단편은 NeuroD1 및 Brn2 전사 인자의 발현을 촉진하는 기능성 단편의 조합 또는 Gsx1 및 Tbr1 전사 인자의 발현을 촉진하는 기능적 단편의 조합 또는 Dlx2 및 Ptf1a 전사 인자의 발현을 촉진하는 기능적 단편의 조합, 또는 Pax6 및 Otx2 전사 인자의 발현을 촉진하는 기능적 단편의 조합으로부터 선택된다.
신경아교세포의 전환 분화 또는 전사 인자의 발현을 상승적으로 촉진할 수 있는 기능성 단편은 전사 인자를 코딩하는 폴리뉴클레오티드 또는 올리고뉴클레오티드로부터 번역되는 기능성 단백질 및 펩티드일 수 있고, 또는 저분자 약물, 고분자 약물, 전사 인자의 발현을 촉진하는 핵산 약물일 수 있으며, 또는 전사 인자의 상류에 위치하고 전사 인자 발현의 상향 조절을 조절할 수 있는 폴리뉴클레오티드 또는 기능성 단백질, 펩티드, 소분자 약물 또는 거대분자 약물, 핵산 약물 등일 수 있다.
다른 우선 예시에서, 신경아교세포 세포의 이기능적 전환을 협동적으로 촉진할 수 있는 기능성 단편 또는 전사 인자 발현을 촉진할 수 있는 기능성 세그먼트는 NeuroD1, Brn2, Ascl1, Ngn2, Gsx1, Tbr1, Dlx2, Ptf1a, Pax6 및/또는 Otx2의 기능성 단백질 또는 NeuroD1, Brn2, Ascl1, Ngn2, Gsx1, Tbr1, Dlx2, Ptf1a, Pax6 및/또는 Otx2와 같은 전사 인자의 기능성 단백질을 부호화하는 뉴크레아 산 염기서열이다. 신경아교세포 세포의 이기능적 전환을 협동적으로 촉진할 수 있는 기능성 단편 또는 전사 인자 발현을 촉진할 수 있는 기능성 세그먼트는 포유동물에서 유래되었으며, 더 선호적으로 인간이나 영장류 이외의 포유동물에서 유래된다. 다른 우선 예시에서는, 기능성 단편의 조합은 다음 그룹에서 선택된다.
(Z1) NeuroD1+Brn2;
(Z2) Ascl1+Ngn2;
(Z3) Ngn2+NeuroD1;
(Z4) Gsx1+Tbr1;
(Z5) Dlx2+Ptf1a;
(Z6) Pax6+Otx2;
(Zn) 은 상기 (Z1) 내지 (Z6) 의 조합.
다른 우선 예시에서는, 기능성 단편의 조합은 다음 그룹에서 선택된다: NeuroD1+Brn2; Gsx1+Tbr1; Dlx2+Ptf1a; Pax6+Otx2 또는 그 조합이다.
다른 우선 예시에서는, 신경아교세포 세포의 이기능적 전환을 협동적으로 촉진할 수 있는 기능성 단편 또는 전사 인자 발현을 촉진할 수 있는 기능성 단편은 기능성 NeuroD1 단백질이며, 단백질 서열은 SEQ ID NO.: 1 또는 SEQ ID NO.: 2이다. NeuroD1 기능성 단백질을 부호화하는 폴리뉴클레오티드 염기서열은 SEQ ID NO.: 3 또는 SEQ ID NO.: 4에 나와 있다.
다른 우선 예시에서는, 신경아교세포 세포의 이기능적 전환을 협동적으로 촉진할 수 있는 기능성 단편 또는 전사 인자 발현을 촉진할 수 있는 기능성 단편은 기능성 Brn2 단백질이며, 단백질 서열은 SEQ ID NO.: 5 또는 SEQ ID NO.: 6이다. Brn2 기능성 단백질을 부호화하는 폴리뉴클레오티드 염기서열은 SEQ ID NO.: 7 또는 SEQ ID NO.: 8에 나와 있다.
다른 우선 예시에서는, 신경아교세포 세포의 이기능적 전환을 협동적으로 촉진할 수 있는 기능성 단편 또는 전사 인자 발현을 촉진할 수 있는 기능성 단편은 기능성 Ascl1 단백질이며, 단백질 서열은 SEQ ID NO.: 9, SEQ ID NO.: 10 또는 SEQ ID NO.: 41이다. Ascl1 기능성 단백질을 부호화하는 폴리뉴클레오티드 염기서열은 SEQ ID NO.: 11 또는 SEQ ID NO.: 12에 나와 있다.
다른 우선 예시에서는, 신경아교세포 세포의 이기능적 전환을 협동적으로 촉진할 수 있는 기능성 단편 또는 전사 인자 발현을 촉진할 수 있는 기능성 단편은 기능성 Ngn2 단백질이며, 단백질 서열은 SEQ ID NO.: 13 또는 SEQ ID NO.: 14이다. Ngn2 기능성 단백질을 부호화하는 폴리뉴클레오티드 염기서열은 SEQ ID NO.: 15 또는 SEQ ID NO.: 16에 나와 있다.
다른 우선 예시에서는, 신경아교세포 세포의 이기능적 전환을 협동적으로 촉진할 수 있는 기능성 단편 또는 전사 인자 발현을 촉진할 수 있는 기능성 단편은 기능성 Gsx1 단백질이며, 단백질 서열은 SEQ ID NO.: 17 또는 SEQ ID NO.: 18이다. Gsx1 기능성 단백질을 부호화하는 폴리뉴클레오티드 염기서열은 SEQ ID NO.: 19 또는 SEQ ID NO.: 20에 나와 있다.
다른 우선 예시에서는, 신경아교세포 세포의 이기능적 전환을 협동적으로 촉진할 수 있는 기능성 단편 또는 전사 인자 발현을 촉진할 수 있는 기능성 단편은 기능성 Tbr1 단백질이며, 단백질 서열은 SEQ ID NO.: 21 또는 SEQ ID NO.: 22이다. Tbr1 기능성 단백질을 부호화하는 폴리뉴클레오티드 염기서열은 SEQ ID NO.: 23 또는 SEQ ID NO.: 24에 나와 있다.
다른 우선 예시에서는, 신경아교세포 세포의 이기능적 전환을 협동적으로 촉진할 수 있는 기능성 단편 또는 전사 인자 발현을 촉진할 수 있는 기능성 단편은 기능성 Dlx2 단백질이며, 단백질 서열은 SEQ ID NO.: 25 또는 SEQ ID NO.: 26이다. Dlx2 기능성 단백질을 부호화하는 폴리뉴클레오티드 염기서열은 SEQ ID NO.: 27 또는 SEQ ID NO.: 28에 나와 있다.
다른 우선 예시에서는, 신경아교세포 세포의 이기능적 전환을 협동적으로 촉진할 수 있는 기능성 단편 또는 전사 인자 발현을 촉진할 수 있는 기능성 단편은 기능성 Ptf1a 단백질이며, 단백질 서열은 SEQ ID NO.: 29 또는 SEQ ID NO.: 30이다. Ptf1a 기능성 단백질을 부호화하는 폴리뉴클레오티드 염기서열은 SEQ ID NO.: 31 또는 SEQ ID NO.: 32에 나와 있다.
다른 우선 예시에서는, 신경아교세포 세포의 이기능적 전환을 협동적으로 촉진할 수 있는 기능성 단편 또는 전사 인자 발현을 촉진할 수 있는 기능성 단편은 기능성 Pax6 단백질이며, 단백질 서열은 SEQ ID NO.: 33 또는 SEQ ID NO.: 34이다. Pax6 기능성 단백질을 부호화하는 폴리뉴클레오티드 염기서열은 SEQ ID NO.: 35 또는 SEQ ID NO.: 36에 나와 있다.
다른 우선 예시에서는, 신경아교세포 세포의 이기능적 전환을 협동적으로 촉진할 수 있는 기능성 단편 또는 전사 인자 발현을 촉진할 수 있는 기능성 단편은 기능성 Otx2 단백질이며, 단백질 서열은 SEQ ID NO.: 37 또는 SEQ ID NO.: 38이다. Otx2 기능성 단백질을 부호화하는 폴리뉴클레오티드 염기서열은 SEQ ID NO.: 39 또는 SEQ ID NO.: 40에 나와 있다.
다른 우선 예시에서는, 신경아교세포 세포의 이기능적 전환을 협동적으로 촉진할 수 있는 기능성 단편 또는 전사 인자 발현을 촉진할 수 있는 기능성 단편은 수정된 Ascl1 기능성 단백질이며, 단백질 서열은 SEQ ID NO.: 41에 나와 있다.
다른 우선 예시에서는, 신경아교세포 세포의 이기능적 전환을 협동적으로 촉진할 수 있는 기능성 단편 또는 전사 인자 발현을 촉진할 수 있는 기능성 단편이 기능성 단백질인 경우, 이 기능성 단백질 서열과 SEQ ID NO.: 1, 2, 5, 6, 9, 10, 13, 14, 17, 18, 21, 22, 25, 26, 29, 30, 33, 34, 37, 38, 41 중 하나의 서열과의 동일성이 85% 이상이 되도록 한다. 더욱 선호되는 실시 예시에서는, 이 기능성 단백질 서열과 SEQ ID NO.: 1, 2, 5, 6, 9, 10, 13, 14, 17, 18, 21, 22, 25, 26, 29, 30, 33, 34, 37, 38, 41 중 하나의 서열과의 동일성이 95% 이상이 되도록 한다. 기능성 단백질과 SEQ ID NO.: 1, 2, 5, 6, 9, 10, 13, 14, 17, 18, 21, 22, 25, 26, 29, 30, 33, 34, 37, 38, 41 중 하나의 서열과의 서열 동일성은 99% 이상이 되도록 하는 것이 선호된다.
다른 우선 예시에서는, 신경아교세포 세포의 이기능적 전환을 협동적으로 촉진할 수 있는 기능성 단편 또는 전사 인자 발현을 촉진할 수 있는 기능성 단편이 기능성 단백질을 부호화하는 폴리뉴클레오티드 염기서열인 경우, 이 폴리뉴클레오티드 염기서열과 SEQ ID NO.: 3, 4, 7, 8, 11, 12, 15, 16, 19, 20, 23, 24, 27, 28, 31, 32, 35, 36, 39, 40 중 하나의 서열과의 동일성이 75% 이상이 되도록 합니다. 더욱 선호되는 실시 예시에서는, 이 폴리뉴클레오티드 염기서열과 SEQ ID NO.: 3, 4, 7, 8, 11, 12, 15, 16, 19, 20, 23, 24, 27, 28, 31, 32, 35, 36, 39, 40 중 하나의 서열과의 동일성이 85% 이상이 되도록 한다. 이 폴리뉴클레오티드 염기서열과 SEQ ID NO.: 3, 4, 7, 8, 11, 12, 15, 16, 19, 20, 23, 24, 27, 28, 31, 32, 35, 36, 39, 40 중 하나의 서열과의 동일성이 95% 이상이 되도록 하는 것이 선호된다.
선호되는 실시 예시에서는, 신경아교세포, NG2 아교세포, 올리고데드로사이트, 마이크로그리아세포, 부상 상태의 아교세포, 아교세포에서 유래한 종양 세포 등 인간이나 비인간 포유류로부터 유래한 어떠한 글리아 세포도 사용할 수 있다. 부상 상태의 글리아 세포는 글리아 세포의 조직 또는 주변 환경이 기계적 외상, 뇌졸중 또는 신경세포의 죽음 및 아포토시스를 유발하는 신경병적 질환 상태로 되어있는 상태의 글리아 세포를 말한다. 이는 신경 신호 전달의 방해 또는 장애를 일으킨다. 글리아 세포에서 유래한 종양 세포는 일반적으로 인간이나 비인간 포유류로부터 유래한 아스트로사이토마, 올리고덴드로그리오마, 전침판 종양, 혼합 글리오마, 조현성 융기종, 불확실한 기원의 신경상피종, 뉴런과 신경교세포의 혼합 종양, 장파상 부인선종, 배아성 종양 및 신경아세포종양에서 선택된다.
선호되는 실시 예시에서, 기능성 신경 세포 또는 뉴로이드 세포는 다음 중 하나 이상의 특징을 포함한다:
(1) 신경 세포의 형태와 유사하다.
(2) 신경 세포 특이 유전자 발현 수준이 상승한다. 상승한 유전자는 DCX, Tuj1, Map2, NeuN, Synapsin I (synaptophysin 1 항체) 중 하나 이상을 포함한다.
(3) 글리아 세포 특이 유전자 발현 수준이 하강합니다. 하강한 유전자는 GFAP, S100 β, Glast 및 Acsbg1 중 하나 이상을 포함한다.
(4) 신경 세포의 전기 생리학적 특성; 즉, 세포는 흥분성 신경전달물질 또는 억제성 신경전달물질의 작용으로 안정전위와 작동전위를 유발한다. 생성된 세포 안정전위는 -50 mV 이상이 되지 않으며, 좀 더 선호적으로는 -55 mV 이상, 또는 -60 mV 이상, 또는 -65 mV 이상이 되지 않는다. 흥분성 신경전달물질에는 제한되지 않으며, 글루타메이트 또는 카이네이트 등이 포함되며, 이러한 신경전달물질은 내부 전류를 유발할 수 있다. 억제성 신경전달물질에는 글리신 또는 γ-아미노뷰티릭 산 (GABA) 등이 포함되며, 이러한 신경전달물질은 외부 전류를 유발할 수 있다.
(5) 기능적 시냅스 형성; 시냅스는 흥분성 또는 억제성 신호 입력을 받고 작동전위를 출력할 수 있다.
본 발명의 두 번째 측면은, 신경세포나 신경 세포 유사세포로의 기능적 재생 프로그램을 위해 교세포와 글리아 세포의 전환을 촉진하는 방법을 제공한다.다른 선호적인 예에서, 이 방법은 비치료적이고 비진단적이다.다른 선호적인 예에서, 이 방법은 체외에서 수행된다.다른 선호적인 예에서, 이 방법은 치료적이다.다른 선호적인 예에서, 이 방법은 다음 단계를 포함한다: 신경아교세포에게 또는 전달 시스템을 이용하여 신경아교세포 내로 적합한 조건에서 교세포 전환을 촉진할 수 있는 본 발명의 첫 번째 측면의 기능성 단편과 접촉시키는 것으로, 신경아교세포를 기능적인 신경세포나 신경 세포 유사세포로 전환 및 재프로그래밍할 수 있다.
본 발명의 두 번째 측면은, 신경세포나 신경 세포 유사세포로의 기능적 재생 프로그램을 위해 교세포와 글리아 세포의 전환을 촉진하는 방법을 제공한다.다른 선호적인 예에서, 이 방법은 비치료적이고 비진단적이다.다른 선호적인 예에서, 이 방법은 체외에서 수행된다.다른 선호적인 예에서, 이 방법은 치료적이다.다른 선호적인 예에서, 이 방법은 다음 단계를 포함한다: 신경아교세포에게 또는 전달 시스템을 이용하여 신경아교세포 내로 적합한 조건에서 교세포 전환을 촉진할 수 있는 본 발명의 첫 번째 측면의 기능성 단편과 접촉시키는 것으로, 신경아교세포를 기능적인 신경세포나 신경 세포 유사세포로 전환 및 재프로그래밍할 수 있다.
바람직하게는, 신경아교세포는 손상된 상태의 임의의 성상세포, NG2 아교세포, 희소돌기아교세포, 미세아교세포 또는 아교세포, 인간 또는 비인간 포유동물의 신경교세포로부터 유래된 종양 세포; 손상 상태의 신경아교세포는 신경교세포의 조직 또는 주변 환경이 기계적 외상, 뇌졸중 또는 신경퇴행성 질환을 일으켜 신경사멸 및 세포사멸을 일으키는 상태에 있는 신경교세포이며, 신경 신호 전달의 막힘 또는 장애를 초래한다.
신경아교세포 유래 종양세포는 일반적으로 성상세포종, 핍지교종, 뇌실막종, 혼합 신경교종, 맥락총 종양, 기원 불확실한 신경상피 조직종, 신경과 신경아교의 혼합 종양, 송과체 실질 종양, 인간 또는 비인간 포유동물로부터 유래된 배아 종양 및 신경모세포종 종양이다
직접적인 접촉 또는 신경아교세포에 소개하여 NeuroD1, Brn2, Ascl1, Ngn2, Gsx1, Tbr1, Dlx2, Ptf1a, Pax6, Otx2 전사 인자 중 어떤 것이든 증가시키는 것을 포함하여 glial 세포의 전사 인자 발현을 증가시키는 어떠한 방법도 가능하다. 이로써 신경아교세포를 기능적 신경세포 또는 뉴로 유사 세포의 특성을 나타내도록 촉진할 수 있다.
전사인자 발현을 촉진하는 유도인자나 기능성 단편은 해당 전사인자를 인코딩하는 폴리뉴클레오티드, 또는 폴리뉴클레오티드 번역 이후의 기능성 단백질 또는 폴리펩타이드, 또는 어떠한 NeuroD1, Brn2, Ascl1, Ngn2, Gsx1, Tbr1, Dlx2, Ptf1a, Pax6, Otx2 전사인자 발현을 촉진하는 소분자 약물, 대분자 약물, 핵산 약물일 수 있으며, 또는 NeuroD1, Brn2, Ascl1, Ngn2, Gsx1, Tbr1, Dlx2, Ptf1a, Pax6, Otx2 전사인자 중 어떤 것의 업스트림에 위치한 폴리뉴클레오티드나 기능성 단백질, 펩타이드, 소분자 약물, 대분자 약물, 핵산 약물일 수 있으며, 이들은 해당 전사인자의 발현 촉진을 조절한다. 유도인자나 전사인자 발현을 촉진하는 기능성 단편은 신경아교세포에 흡수되거나 전달 시스템을 통해 신경아교세포에 도달하여 작용한다.
신경아교세포의 전환을 촉진할 수 있는 전사 인자 발현을 촉진하는 유도 인자 또는 기능적 단편은, 전사 인자를 인코딩하는 폴리뉴클레오티드, 또는 폴리뉴클레오티드의 번역 이후 기능적 단백질 또는 폴리펩타이드, 또는 NeuroD1, Brn2, Ascl1, Ngn2, Gsx1, Tbr1, Dlx2, Ptf1a, Pax6, Otx2 중 어떤 전사 인자의 발현을 촉진하는 소분자 약물, 대형 분자 약물, 핵산 약물 등이 될 수 있으며, 또는 NeuroD1, Brn2, Ascl1, Ngn2, Gsx1, Tbr1, Dlx2, Ptf1a, Pax6, Otx2 중 어떤 전사 인자의 upstream에 위치한 폴리뉴클레오티드 또는 기능적 단백질, 펩타이드, 소분자 약물 또는 대형 분자 약물, 핵산 약물도 포함된다. 전사 인자의 발현을 조절하며, 신경아교세포에 수동적으로 흡수되거나 전달 시스템을 통해 도달하여 작용한다.
전달 시스템은, 트랜스크립션 팩터의 발현을 촉진하는 기능적 단편을 포함하는 발현 벡터, 기능적 단편이 포함된 나노입자, 기능적 단편이 포함된 외부 소포체, 바이러스 벡터 또는 세포 벡터 (수정된 적혈구 또는 박테리아 등)을 포함할 수 있으며, 기능적 단편이 포함된 특이적 영향체 (신경아교세포 특이적 항체, 폴리펩타이드 또는 기타 특이적 물질)도 포함될 수 있다.
또 다른 우선적인 예시로, inducer 또는 transcription factor 발현 촉진제의 기능적 단편은 트랜스크립션 팩터를 인코딩하는 폴리뉴클레오티드이며, 이러한 폴리뉴클레올티드는 NeuroD1, Brn2, Ascl1, Ngn2, Gsx1, Tbr1, Dlx2, Ptf1a, Pax6 및/또는 Otx2의 트랜스크립션 팩터 기능적 폴리뉴클레올티드로 선택됩니다. 이러한 폴리뉴클레올티드는 바이러스성 또는 비바이러스성 전달 시스템에 로드되어야 한다.
또 다른 우선적인 예시로, 전달 시스템에는 플라스미드, 바이러스 및 세포 벡터가 포함될 수 있으며, 선호되는 바이러스 벡터는 아데노 바이러스 벡터, 아데노관련 바이러스 벡터 (AAV), 레트로바이러스 발현 벡터 또는 렌티바이러스 벡터 등이 있다.
다른 우선적인 예시에서는, 전사 인자 폴리뉴클레오티드를 포함하는 발현 벡터는 신경아교세포 특이적 프로모터도 함께 포함한다. 이러한 프로모터에는 GFAP 프로모터, NG2 프로모터, Aldh1L1 프로모터, IBA1 프로모터, CNP 프로모터, LCN2 프로모터 또는 유전자 조작 후 변종 프로모터 등이 포함된다.
다른 우선적인 예시에서는, 프로모터가 GFAP 프로모터이며, 유전자 조작 후의 GFAP 프로모터이다. 선호적으로, 인간 hGFAP 프로모터(SEQ ID No: 42)는 683 bp의 절단 버전(SEQ ID No: 43)으로 변환될 수 있다.
다른 우선적인 예시에서는, 전사 인자 폴리뉴클레오티드를 포함하는 발현 벡터는 유전자 발현 조절에 기여하는 하나 이상의 조절 요소도 포함한다. 이러한 조절 요소에는 CMV 개선자, SV40 개선자, EN1 개선자, VP16 융합 단백질 또는 유전자 조작 후의 개선자 변종, 그리고 SV40 폴리A 꼬리 신호, 인간 인슐린 유전자 폴리A 꼬리 신호 또는 marmot hepatitis B 바이러스의 전사 후 조절 요소(WPRE), 인간 MAR 서열 또는 유전자 조작 후의 변종 등이 포함된다.
다른 우선적인 예시에서는, 발현 증가를 위해 사용되는 조절 요소는 대상 단백질 16의 활성 도메인(SEQ ID NO: 44) 이다. 여기서 VP16의 코딩 서열(SEQ ID NO: 45)은 개별적으로 또는 연속적으로 적재될 수 있으며, VP16-전사 인자 DNA 결합 영역의 융합 단백질은 신경아교세포 특이적 프로모터를 통해 발현될 수 있다.
다른 바람직한 예에서, 발현을 향상시키기 위해 사용되는 조절 요소는 유인원 액포화 바이러스 40 SV40(SEQ ID NO: 46)의 인핸서로부터 유래한다. 신경아교세포 특이적 프로모터에 삽입하면 프로모터의 활성을 높이고 뉴런 유도 효율을 높일 수 있다.
다른 예시로, 발현 인자를 포함한 발현 벡터는 동시에 다른 기능적 단편을 포함할 수도 있다. 이 다른 기능적 단편은 리포터 유전자이거나 재프로그래밍 기능을 가진 다른 전사 인자 기능적 단편일 수 있으며, NeuroD1, Brn2, Ascl1, Ngn2, Gsx1, Tbr1, Dlx2, Ptf1a, Pax6, Otx2 등에서 선택된다. 가능한 경우 같은 벡터는 하나의 아교세포-특이적 프로모터 하에 또는 두 개의 아교세포-특이적 프로모터 하에 적어도 두 개의 전사 인자의 폴리뉴클레오티드 단편을 포함할 수 있다. 두 개 이상의 전사 인자가 단일 프로모터의 전사체 내에서 표현되는 경우, 프로모터는 여러 개의 cis-transon 요소를 통해 여러 전사 인자의 오픈 리딩 프레임과 연결된다. 그 중, 전사 인자는 IRES 또는 2A 폴리펩타이드(P2A) 요소로 분리되어 다중 전사 인자의 발현을 달성한다. 이 중에서도, 두 전사 인자의 조합은 NeuroD1과 Brn2 전사 인자의 조합, Gsx1과 Tbr1 전사 인자의 조합, Dlx2와 Ptf1a 전사 인자의 조합, Pax6과 Otx2 전사 인자의 조합, Ascl1과 Ngn2 전사 인자의 조합 중에서 선택된다. 두 전사 인자의 몰 농도 비는 4:1~1:4이다. 가능한 경우, 두 전사 인자의 발현 양의 몰 농도 비는 2:1에서 1:2로 선택된다. 더 나아가, 최적의 두 전사 인자의 발현 양의 몰 농도 비는 1:1이다.
다음의 선호되는 예시 중 하나는, 동일한 벡터가 적어도 두 개의 전사 인자를 포함하며, 그 중 하나는 Ascl1 또는 Ngn2인 경우이다. 이 경우 Ascl1 또는 Ngn2의 발현 양의 몰 농도 비율은 20% 이하가 아니다. 발현 양의 몰 농도 비율은 33% 이하가 아니면 좋으며, 더 나아가 50% 이하가 아니면 좋다. 벡터는 다음의 전사 인자들의 어떤 조합이든 포함할 수 있다:
(1) Ascl1와 NeuroD1, Brn2, Ascl1, Ngn2, Gsx1, Tbr1, Dlx2, Ptf1a, Pax6 또는 Otx2 중에서 다른 어떤 전사 인자와의 결합;
(2) Ngn2와 NeuroD1, Brn2, Ascl1, Ngn2, Gsx1, Tbr1, Dlx2, Ptf1a, Pax6 또는 Otx2 중에서 다른 어떤 전사 인자와의 결합; 그리고
(3) 최소한 세 개의 전사 인자를 동일한 벡터에 담을 때, 전사 인자는 Ascl1+NeuroD1+Brn2, Ascl1+Gsx1+Tbr1, Ascl1+Dlx2+Ptf1a, Ascl1+Pax6+Otx2, Ngn2+NeuroD1+Brn2, Ngn2+Gsx1+Tbr1, Ngn2+Dlx2+Ptf1a, 또는 Ngn2+Pax6+Otx2의 결합을 포함해야 한다. 여기에서, Ascl1 또는 Ngn2를 제외한 나머지 두 전사 인자의 몰 농도 비는 4:1에서 1:4 사이여야 한다. 가능하면, 두 전사 인자의 표현 양의 몰 농도 비는 2:1에서 1:2여야 하며, 더 나아가서는 두 전사 인자의 표현 몰 농도 비가 1:1이어야 한다.
다른 선호적인 예로는, 서로 다른 전사 인자 폴리뉴클레오티드를 포함하는 하나 이상의 발현 벡터를 동시에 사용할 수 있다. 전사 인자는 NeuroD1, Brn2, Ascl1, Ngn2, Gsx1, Tbr1, Dlx2, Ptf1a, Pax6 및/또는 Otx2의 전사 인자 기능 폴리뉴클레오티드에서 선택된다. 이 때, 벡터 조합은 NeuroD1 전사 인자와 Brn2 전사 인자를 포함하는 벡터 조합, Gsx1 전사 인자와 Tbr1 전사 인자를 포함하는 벡터 조합, Dlx2 전사 인자와 Ptf1a 전사 인자를 포함하는 벡터 조합, Pax6 전사 인자와 Otx2 전사 인자를 포함하는 벡터 조합 중에서 선택된다. 두 전사 인자의 발현 모랄 농도 비율은 4:1~1:4이다. 발현 양의 두 전사 인자의 발현 모랄 농도 비율은 2:1에서 1:2이다. 더욱 선호적으로, 두 전사 인자의 발현 양의 최적 모랄 농도 비율은 1:1이다.
또 다른 바람직한 예에서, 적어도 Ascl1 또는 Ngn2 폴리뉴클레오티드를 포함하는 발현 벡터와 다른 전사 인자 벡터의 조합을 포함하여, 상이한 전사 인자 폴리뉴클레오티드를 포함하는 하나 이상의 발현 벡터가 동시에 사용될 수 있다.
여기서 Ascl1 또는 Ngn2 발현량의 몰농도비는 20% 이상이어야 하고, 바람직하게는 Ascl1 또는 Ngn2 발현량의 몰농도비는 33% 이상이어야 하며;
더욱 바람직하게는, Ascl1 또는 Ngn2의 발현량의 몰 농도 비율은 50% 이상이어야 하고; 발현 벡터는 다음 벡터의 조합에서 선택됩니다.
(1) 전사 인자 Ascl1과 NeuroD1, Brn2, Ascl1, Ngn2, Gsx1, Tbr1, Dlx2, Ptf1a, Pax6 또는 Otx2에서 선택되는 다른 전사 인자를 포함하는 벡터의 조합;
(2) 전사 인자 Ngn2를 포함하는 벡터는 NeuroD1, Brn2, Ascl1, Ngn2, Gsx1, Tbr1, Dlx2, Ptf1a, Pax6 또는 Otx2 중에서 선택되는 다른 전사 인자를 포함하는 벡터와 결합된다;
(3) 전사 인자 Ascl1, NeuroD1 및 Brn2를 포함하는 벡터 조합, 전사 인자 Ascl1, Gsx1 및 Tbr1을 포함하는 벡터 조합, 전사 인자 Ascl1, Dlx2 및 Ptf1a를 포함하는 벡터 조합, 전사 인자 Ascl1, Pax6 및 Otx2를 포함하는 벡터 조합 또는 전사 인자 Ngn2, NeuroD1 및 Brn2를 포함하는 벡터 조합, 전사 인자 Ngn2, Gsx1 및 Tbr1을 포함하는 벡터 조합, 전사 인자 Ngn2, Dlx2 및 Ptf1a를 포함하는 벡터 조합 전사 인자 Ngn2, Pax6 및 Otx2를 포함하는 벡터 조합을 포함할 수 있다.
그 중 Ascl1이나 Ngn2를 제외한 나머지 두 전사인자의 발현 몰농도비는 4:1 내지 1:4이고; 바람직하게는, 두 전사 인자의 발현량의 몰 농도비는 2:1 내지 1:2; 더욱 바람직하게는 2종의 전사인자의 발현량의 몰농도비가 1:1이다.
다른 바람직한 예에서, 전사 인자 폴리뉴클레오티드를 포함하는 기능성 단편의 발현 벡터는 렌티바이러스 벡터이고; 렌티바이러스 벡터는 바이러스 ITR 서열, CAG 프로모터, 전사 인자 폴리뉴클레오티드의 기능적 단편의 코딩 프레임, 전사 후 조절 요소 WPRE 등을 포함한다.
발현 벡터는 또한 리포터 유전자를 포함할 수 있지만, 실제 적용에서 리포터 유전자는 필요하지 않다. 5'에서 3' 말단까지의 렌티바이러스 벡터는 다음 요소를 연속적으로 포함할 수 있다: 바이러스 ITR 서열 + CAG 프로모터 + 전사 인자 폴리뉴클레오티드 및 녹색 형광 단백질 GFP의 코딩 프레임 + 전사후 조절 요소 WPRE + 바이러스 ITR 서열 + 암피실린 내성 유전자의 프로모터 및 코딩 프레임. 이 중 GFP의 코딩 프레임과 암피실린 내성 유전자의 프로모터 및 코딩 프레임은 필요하지 않다. 바람직하게는, 전사 인자의 폴리뉴클레오티드는 NeuroD1, Brn2, Ascl1, Ngn2, Gsx1, Tbr1, Dlx2, Ptf1a, Pax6 및/또는 Otx2를 암호화하는 기능성 폴리뉴클레오티드; 구체적으로, 서열번호: 3, 4, 7, 8, 11, 12, 15, 16, 19, 20, 23, 24, 27, 28, 31, 32, 35, 36, 39 및/또는 또는 40.
다른 바람직한 예에서, 전사 인자 폴리뉴클레오티드를 포함하는 기능성 단편의 발현 벡터는 GFAP-AAV 벡터이고; GFAP-AAV 벡터는 바이러스 ITR 서열, CMV 인핸서, 인간 GFAP 프로모터, 전사 인자 폴리뉴클레오티드의 기능적 단편의 코딩 프레임, 전사후 조절 요소 WPRE 등을 포함하고; 발현 벡터는 또한 리포터 유전자를 포함할 수 있지만, 실제 적용에서 리포터 유전자는 필요하지 않다. GFAP-AAV 발현 벡터는 5'에서 3' 말단까지 다음 요소를 연속적으로 포함할 수 있다: 바이러스 ITR 서열 + CMV 인핸서 + 인간 GFAP 프로모터 + 적색 형광 단백질 mCherry의 전사 인자 폴리뉴클레오티드 및 코딩 프레임 + 전사후 조절 요소 WPRE + 바이러스 ITR 서열 + 암피실린 내성 유전자의 프로모터 및 코딩 프레임,여기서 적색 형광 단백질 mCherry의 코딩 프레임 및 암피실린 내성 유전자의 프로모터 및 코딩 프레임은 필요하지 않다. 바람직하게는, 전사 인자의 폴리뉴클레오티드는 NeuroD1, Brn2, Ascl1, Ngn2, Gsx1, Tbr1, Dlx2, Ptf1a, Pax6 및/또는 Otx2를 암호화하는 기능성 폴리뉴클레오티드로부터 선택된다. 구체적으로, SEQ ID NO.: 3, 4, 7, 8, 11, 12, 15, 16, 19, 20, 23, 24, 27, 28, 31, 32, 35, 36, 39 및/또는 또는 40.
다른 바람직한 예에서, GFAP-AAV 발현 벡터는 5'에서 3' 말단으로부터 다음 요소를 포함할 수 있다: 바이러스 ITR 서열 + SV40 인핸서 + 인간 GFAP 프로모터 + 전사 인자 폴리뉴클레오티드 + 전사후 조절 요소 WPRE + 바이러스 ITR 서열.
다른 바람직한 예에서, GFAP-AAV 발현 벡터는 5'에서 3' 말단으로 차례로 다음 요소를 포함할 수 있다: 바이러스 ITR 서열 + CMV 인핸서 + 인간 GFAP 프로모터 + VP16 융합 단백질 + 전사 인자의 DNA 결합 영역 + 포스트 전사 조절 요소 WPRE + 바이러스 ITR 서열.
다른 바람직한 예에서, GFAP-AAV 발현 벡터는 5'에서 3' 말단으로부터 다음 요소를 포함할 수 있다: 바이러스 ITR 서열 + CMV 인핸서 + 인간 절단 GFAP 프로모터 + 전사 인자 폴리뉴클레오티드 + 전사후 조절 요소 WPRE + 바이러스 ITR 서열 .
다른 바람직한 예에서, 5'에서 3' 말단으로의 GFAP-AAV 발현 벡터는 연속적으로 다음 요소를 포함할 수 있다: 바이러스 ITR 서열 + SV40의 인핸서 + 인간 절단된 GFAP의 프로모터 + VP16 융합 단백질 + 전사 인자의 DNA 결합 영역 + 전사 후 조절 요소 WPRE + 바이러스 ITR 서열.
다른 바람직한 예에서, GFAP-AAV 발현 벡터는 5'에서 3' 말단으로부터 다음 요소를 포함할 수 있다: 바이러스 ITR 서열 + SV40 인핸서 + 인간 절단 GFAP 프로모터 + 전사 인자 폴리뉴클레오티드 + 전사 후 조절 요소 WPRE + 바이러스 ITR 서열 .
또 다른 바람직한 예에서, GFAP-AAV 발현 벡터는 5'에서 3' 말단으로 차례로 다음 요소를 포함할 수 있다: 바이러스 ITR 서열 + SV40의 인핸서 + 인간 GFAP의 프로모터 + VP16 융합 단백질 + 전사 인자의 DNA 결합 영역 + 전사 후 조절 요소 WPRE + 바이러스 ITR 서열.
다른 바람직한 예에서, GFAP-AAV 발현 벡터는 5'에서 3' 말단으로 차례로 다음 요소를 포함할 수 있다: 바이러스 ITR 서열 + CMV 인핸서 + 인간 절단 GFAP 프로모터 + VP16 융합 단백질 + 전사 인자의 DNA 결합 영역 + 전사 후 조절 요소 WPRE + 바이러스 ITR 서열.
본 발명의 세 번째 측면은 다음을 포함하는 약제학적 조성물을 제공한다:
(A) 본 발명의 제1 측면에 기재된 전사 인자의 발현을 촉진하는 기능적 단편; 및/또는
(B) 본 발명의 제2측면에 기재된 방법에 의해 아교세포 전환분화 및 리프로그래밍을 촉진하여 얻어지는 기능성 뉴런 또는 뉴런 유사 세포; 그리고
(C) 약제학적으로 허용되는 부형제.
다른 바람직한 예에서, 약제학적 조성물은 액체 제제 및 동결건조 제제이다.
다른 바람직한 예에서, 약제학적 조성물은 주사제이다.
다른 바람직한 예에서, 약제학적 조성물은 다음을 포함한다:
(A) 전사 인자의 발현을 촉진하는 기능적 단편의 조합, 또는 기능적 뉴런 또는 뉴런 유사 세포로서, 상기 기능적 단편의 조합으로 신경아교세포를 가공하여 전환분화 및 재프로그래밍함으로써 얻어지는 것;
여기서, 조합은 Ascl1 또는 향상된 Ascl1을 포함하고; 또는 Ngn2; 또는
설명된 조합은 다음 그룹에서 선택된다.
(Z1) NeuroD1+Brn2;
(Z2) Ascl1+Ngn2;
(Z3) Ngn2 + NeuroD1;
(Z4) Gsx1+Tbr1;
(Z5) Dlx2+Ptf1a;
(Z6) Pax6+Otx2; 및
(Zn) 상기 (Z1) 내지 (Z6)의 조합,
(B) 약제학적으로 허용되는 부형제.
다른 바람직한 예에서, 상기 조합은 강화된 Ascl1과 NeuroD1, Brn2, Ngn2, Gsx1, Tbr1, Dlx2, Ptf1a, Pax6, Otx2 그룹으로부터 선택된 적어도 하나의 조합이다.
다른 바람직한 예에서, 상기 조합은 Ascl1과 NeuroD1, Brn2, Ngn2, Gsx1, Tbr1, Dlx2, Ptf1a, Pax6, Otx2 그룹으로부터 선택된 적어도 하나의 조합이다.
다른 바람직한 예에서, 상기 조합은 Ngn2와 NeuroD1, Brn2, Ngn2, Gsx1, Tbr1, Dlx2, Ptf1a, Pax6, Otx2 그룹으로부터 선택된 적어도 하나의 조합이다.
본 발명의 네 번째 양태는 아교세포로부터 전환분화 및 재프로그래밍을 통해 얻은 인공 재프로그래밍된 뉴런 또는 뉴런 유사 세포를 제공한다.
또 다른 바람직한 예에서, 인공 재프로그래밍된 뉴런 또는 뉴런 유사체는 본 발명의 제2 측면에 기재된 방법에 의해 제조된다.
본 발명의 제5 양태는 본 발명의 제3 양태에 기술된 약제학적 조성물 또는 제4 양태의 인공 재프로그래밍된 뉴런 또는 뉴런 유사 세포의 용도를 제공하는데, 즉 이들은 유전자 치료용 약물을 제조하는 데 사용된다. 신경계 질환의. 바람직하게는 신경계 질환은 신경계 손상 또는 신경아교세포 유래 신경아교종이다.
본 발명의 범위 내에서, 본 발명의 상기 기술적 특징 및 다음에 구체적으로 기술된 기술적 특징(실시예에 따라)은 서로 조합되어 새로운 또는 바람직한 기술적 해결책을 형성할 수 있음을 이해해야 한다. 공간이 제한되어 있으므로 여기서는 반복하지 않는다.
도 1은 Brn2와 NeuroD1의 조합이 인간 신경아교종 세포를 뉴런으로 유도할 수 있음을 보여준다. 도1A 내지 C는 대조군 렌티바이러스 FUGW, 단일 바이러스 FUGW - NeuroD1, 및 두 바이러스 FUGW - Brn2 및 FUGW - NeuroD1. 도 1D는 서로 다른 바이러스 유발 뉴런의 비율에 대한 통계 다이어그램을 보여준다. "* *"는 p<0.01을 나타냅니다. 축척: 50μm.
도 2는 Brn2와 NeuroD1의 조합에 의해 유도된 뉴런의 분자 발현 특성을 보여준다. 도 2A는 신경아교종 세포가 렌티바이러스에 감염된 후 21일 후에 유도된 뉴런이 성숙한 뉴런의 마커 분자 MAP2를 발현했음을 보여준다. 도 2B-D는 유도된 뉴런이 성숙한 뉴런의 마커 분자인 Synapsin I을 발현한다는 것을 보여준다. 도 2E-H는 글루타메이트 뉴런 마커 분자 VGLUT1을 발현하는 유도 뉴런의 송신기 특성을 보여준다. 축척: 20μm.
도 3은 Brn2와 NeuroD1의 결합에 의해 유도된 뉴런의 전기생리학적 특성을 보여준다. 도 3A는 유리 전극(녹색 형광 포함)에 의해 기록되는 세포를 보여줍니다. 도 3B는 유도된 뉴런이 활동 전위를 방출할 수 있음을 보여준다. 도 3C는 유도된 뉴런의 시냅스 후 전류 신호가 감지되고 차단제 CNQX 및 AP5를 추가한 후 시냅스 후 전류 신호가 사라지는 것을 보여준다.
도 4는 Brn2와 NeuroD1의 조합이 뉴런이 세포 주기를 벗어나도록 유도함을 보여준다. 도 4A 및 B는 BrdU 간격이 바이러스 감염의 상이한 시기에 표지되었을 때 Brn2/NeuroD1의 조합에 의해 유도된 세포의 BrdU 양성 수가 급격히 감소함을 보여준다. 도 4C-F는 BrdU가 라벨에 지속적으로 통합되었을 때 바이러스 감염 5일 후 Brn2/NeuroD1의 조합에 의해 유도된 BrdU 양성 세포의 수가 크게 감소했음을 보여준다. 도 4F의 화살표는 유도된 뉴런이 BrdU 음성임을 나타낸다. "*"는 p<0.05를 나타낸다. "* *"는 p<0.01을 나타낸다. 축척: 50μm.
도 5는 Brn2와 NeuroD1의 조합이 신경아교종 세포의 성장을 억제함을 보여준다. 도 5A-C는 바이러스 감염 14일 후 Ki67의 면역세포화학적 분석 결과 Brn2/NeuroD1 조합에서 Ki67 양성 세포의 수가 크게 감소했음을 보여준다. 도 5B의 화살표는 유도된 뉴런이 Ki67 음성임을 나타낸다. 도 5D는 바이러스 감염의 다른 시간 후에 계산된 세포의 수를 보여준다. "* *"는 p<0.01을 나타낸다. 축척: 50μm.
도 6은 재프로그래밍 인자 NeuroD1 및 Brn2를 발현하는 AAV 벡터가 전환분화 뉴런을 유도함으로써 동물에서 신경아교종의 성장을 억제함을 보여준다. 도 6A는 상이한 투여군에서 각 시점에서의 종양 부피를 나타내고, 도 6B는 상이한 투여군에서 종양 샘플의 실시간 PCR 분석 결과를 나타낸다. "*"는 p<0.05를 나타낸다.
도 7은 재프로그래밍 인자 NeuroD1 및 Brn2를 발현하는 아데노바이러스 5형이 뉴런의 전환분화를 유도함으로써 동물에서 신경아교종 성장을 억제함을 보여준다. 도 7A는 상이한 투여군에서 각 시점에서의 종양 부피를 나타내고, 도 7B는 상이한 투여군에서 종양 샘플의 HE 색상 결과를 나타낸다. "*"는 p<0.05를 나타낸다.
도 2는 Brn2와 NeuroD1의 조합에 의해 유도된 뉴런의 분자 발현 특성을 보여준다. 도 2A는 신경아교종 세포가 렌티바이러스에 감염된 후 21일 후에 유도된 뉴런이 성숙한 뉴런의 마커 분자 MAP2를 발현했음을 보여준다. 도 2B-D는 유도된 뉴런이 성숙한 뉴런의 마커 분자인 Synapsin I을 발현한다는 것을 보여준다. 도 2E-H는 글루타메이트 뉴런 마커 분자 VGLUT1을 발현하는 유도 뉴런의 송신기 특성을 보여준다. 축척: 20μm.
도 3은 Brn2와 NeuroD1의 결합에 의해 유도된 뉴런의 전기생리학적 특성을 보여준다. 도 3A는 유리 전극(녹색 형광 포함)에 의해 기록되는 세포를 보여줍니다. 도 3B는 유도된 뉴런이 활동 전위를 방출할 수 있음을 보여준다. 도 3C는 유도된 뉴런의 시냅스 후 전류 신호가 감지되고 차단제 CNQX 및 AP5를 추가한 후 시냅스 후 전류 신호가 사라지는 것을 보여준다.
도 4는 Brn2와 NeuroD1의 조합이 뉴런이 세포 주기를 벗어나도록 유도함을 보여준다. 도 4A 및 B는 BrdU 간격이 바이러스 감염의 상이한 시기에 표지되었을 때 Brn2/NeuroD1의 조합에 의해 유도된 세포의 BrdU 양성 수가 급격히 감소함을 보여준다. 도 4C-F는 BrdU가 라벨에 지속적으로 통합되었을 때 바이러스 감염 5일 후 Brn2/NeuroD1의 조합에 의해 유도된 BrdU 양성 세포의 수가 크게 감소했음을 보여준다. 도 4F의 화살표는 유도된 뉴런이 BrdU 음성임을 나타낸다. "*"는 p<0.05를 나타낸다. "* *"는 p<0.01을 나타낸다. 축척: 50μm.
도 5는 Brn2와 NeuroD1의 조합이 신경아교종 세포의 성장을 억제함을 보여준다. 도 5A-C는 바이러스 감염 14일 후 Ki67의 면역세포화학적 분석 결과 Brn2/NeuroD1 조합에서 Ki67 양성 세포의 수가 크게 감소했음을 보여준다. 도 5B의 화살표는 유도된 뉴런이 Ki67 음성임을 나타낸다. 도 5D는 바이러스 감염의 다른 시간 후에 계산된 세포의 수를 보여준다. "* *"는 p<0.01을 나타낸다. 축척: 50μm.
도 6은 재프로그래밍 인자 NeuroD1 및 Brn2를 발현하는 AAV 벡터가 전환분화 뉴런을 유도함으로써 동물에서 신경아교종의 성장을 억제함을 보여준다. 도 6A는 상이한 투여군에서 각 시점에서의 종양 부피를 나타내고, 도 6B는 상이한 투여군에서 종양 샘플의 실시간 PCR 분석 결과를 나타낸다. "*"는 p<0.05를 나타낸다.
도 7은 재프로그래밍 인자 NeuroD1 및 Brn2를 발현하는 아데노바이러스 5형이 뉴런의 전환분화를 유도함으로써 동물에서 신경아교종 성장을 억제함을 보여준다. 도 7A는 상이한 투여군에서 각 시점에서의 종양 부피를 나타내고, 도 7B는 상이한 투여군에서 종양 샘플의 HE 색상 결과를 나타낸다. "*"는 p<0.05를 나타낸다.
전류 신호가 나타나는지 여부를 관찰하여 유도된 뉴런이 신경 회로에 통합되어 시냅스 연결을 확립하는지, 기능적 뉴런인지 여부를 판단한다.
AAV 바이러스는 마우스 뇌 아틀라스를 참조하여 수행되었다. 바이러스 주입 후 등의 중뇌와 척수를 서로 다른 시점에서 채취하여 면역염색 또는 뇌 절편 기록을 실시하였다. 손상되지 않은 척수 및 손상된 척수 바이러스의 주입 농도와 속도는 바늘당 주입량과 뇌 영역과 일치한다. 주사는 척수에서 30°의 각도로 수행되었다.
신경 손상 복구 모델
(1) 척수 손상 및 바이러스 형질감염
마우스의 완전한 척수 손상에 대한 T8-T10 모델이 구성되었다(McDonough A, Monterubio A, Arizona J, et al. Calibrated Forceps Model of Spinal Cord Compression Injury. Jove-Journal of Visualized Experiments 2015의 방법 참조). AAV-mCherry 바이러스 및 AAV-전사 인자/mCherry는 부상 직후 손상된 척수의 양쪽에 주입되었다. mCherry와 NeuN이 바이러스 주입 후 3일 및 바이러스 주입 후 30일에 같은 위치에 있는지 관찰하였다.
(2) 척수 손상의 복구 감지
흉부 척수 손상 후 감각 구 심성 소실은 뇌간의 하강 억제 시스템의 억제 효과를 약화시켜 외부 자극에 대한 꼬리의 과민성을 유발한다. 꼬리 플릭 실험 모델을 사용하여 48℃와 52℃ 열자극 조건에서 두 그룹의 마우스 꼬리 반응의 지연 시간을 측정하여 마우스의 감각 능력을 테스트하였다. 생쥐의 운동 기능은 BMS 표준에 따라 점수를 매겼다. 테스트 방법에 대해서는 Basso Mouse Scale에서 5가지 일반적인 마우스 변종의 최종 코어 조정 후 회복의 국소화 검출 차이를 참조하였다. J Neurotrauma, 2006. 23(5): p. 635-59.
신경교종 모델
신경아교종 모델 이식에 사용된 마우스는 7주의 NOD-scid 마우스였다. 인간 신경교종 세포에 0.25% 트립신 소화 및 유도를 3일 동안 또는 유도 없이 제공하였다. 원심분리 후 상등액을 제거하여 농축 후 세포 밀도가 약 2.5 × 105 cells/μL가 되도록 하였다. 각 마우스 2 μL의 이식 뇌 선조체(총 5개 × 105개 세포). 이식 3주 후에 조직화학검사를 시행하거나 이식 1주일 후 바이러스를 주입한 후 면역조직화학검사를 시행하였다.
실시예
실시예 1: 단일 전사 인자의 기능적 단편은 신경아교세포가 뉴런으로 분화하도록 촉진한다
우선, 우리는 예비 스크리닝을 수행하기 위해 in vitro에서 신경교세포 전환분화 모델을 사용하였고, 신경교세포 전환분화를 유도할 수 있는 전사 인자 배치를 얻었다. 사용된 전사 인자의 코딩 서열 및 변환 효율은 표 1에 제시되어 있다.
In vitro trans-differentiation 효율 % = (양성 신경 마커 Tuj1 및 전기 생리학에 의해 검출 된 자발적 시냅스 후 전류를 갖는 바이러스에 감염된 형광 양성 세포의 수 / 바이러스에 감염된 형광 양성 세포의 총 수) × 100 %, 평균적으로 각 전사 인자에 대해 Tuj1 양성 및 자발적 시냅스후 전류를 갖는 적어도 100개의 전환분화 세포가 검출될 수 있다.
| 전사 인자 | 인간(야생형) | 전환 분화 효율 | 마우스(야생형) | 전환 분화 효율 |
| NeuroD1 | SEQ ID NO: 1/3 | 42.3% | SEQ ID NO: 2/4 | 45.8% |
| Brn2 | SEQ ID NO: 5/7 | 8.7% | SEQ ID NO: 6/8 | 9.6% |
| Ascl1 | SEQ ID NO: 9/11 | 68.5% | SEQ ID NO: 10/12 | 67.3% |
| Ngn2 | SEQ ID NO: 13/15 | 51.2% | SEQ ID NO: 14/16 | 46.3% |
| Gsx1 | SEQ ID NO: 17/19 | 6.2% | SEQ ID NO: 18/20 | 6.9% |
| Tbr1 | SEQ ID NO: 21/23 | 4.2% | SEQ ID NO: 22/24 | 5.3% |
| Dlx2 | SEQ ID NO: 25/27 | 32.1% | SEQ ID NO: 26/28 | 35.7% |
| Ptf1a | SEQ ID NO: 29/31 | 11.6% | SEQ ID NO: 30/32 | 15.3% |
| Pax6 | SEQ ID NO: 33/35 | 25.2% | SEQ ID NO: 34/36 | 19.8% |
| Otx2 | SEQ ID NO: 37/39 | 6.9% | SEQ ID NO: 38/40 | 8.4% |
인간 및 마우스 유래 전사 인자 둘 모두는 시험관내에서 신경아교세포를 뉴런으로 분화시키는 능력을 갖는다.추가 연구에서 우리는 또한 인간 Ascl1 단백질의 경우 단백질 서열의 5개의 보존된 세린-프롤린(SP) 인산화 부위(단백질 서열의 위치 93, 190, 194, 207 및 223에 위치)가 알라닌-프롤린(AP) (향상된 Ascl1(SA-hAscl1) 및 단백질 서열 SEQ ID NO: 41) 으로 돌연변이되면 형질전환 효율이 85.5%까지 더 향상될 수 있음을 발견했다.
실시예 2 단일 전사 인자의 기능적 단편은 등쪽 중뇌에서 신경아교세포 전환분화를 촉진한다. 신경아교세포 전환분화의 생체 내 모델에 따라 하기 표(표 2)와 같이 실시예 1에서 선별된 전사 인자를 이용하여 등쪽 중뇌의 신경아교세포를 유도하고자 하였다. 상이한 전사 인자는 상당히 상이한 형질전환 효율을 나타내었다.
생체내 전환분화의 효율은 뉴런 공동-국소화 발생의 비율에 의해 특징지어진다. 생체내 전환분화 효율 % = (전기생리학으로 검출할 수 있는 양성 뉴런 마커 NeuN 및 자발적 시냅스 후 전류를 갖는 바이러스에 감염된 형광 양성 세포의 수/전체 바이러스에 감염된 형광 양성 세포의 수) × 100%, NeuN 양성 및 자발적 시냅스 후 전류를 갖는 적어도 100개의 전환분화 세포가 평균적으로 각각의 전사 인자에 대해 검출될 수 있다.
| 인간 전사 인자 | 뮤린 전사 인자 | |||
| 신경 공동 위치 | 시냅스 형성 여부 | 신경 공동 위치 | 시냅스 형성 여부 | |
| NeuroD1 | 66.4% | yes | 68.7% | yes |
| Brn2 | 8.4% | yes | 9.3% | yes |
| Ascl1 | 72.8% | yes | 79.1% | yes |
| Ngn2 | 71.2% | yes | 73.5% | yes |
| Gsx1 | 5.1% | yes | 5.7% | yes |
| Tbr1 | 4.4% | yes | 4.8% | yes |
| Dlx2 | 23.6% | yes | 29.4% | yes |
| Ptf1a | 8.2% | yes | 11.3% | yes |
| Pax6 | 21.2% | yes | 24.8% | yes |
| Otx2 | 7.2% | yes | 8.8% | yes |
| 향상된 Ascl1 | 86.6% | yes | 83.6% | yes |
생체 내 모델을 기반으로 AAV 발현 벡터의 발현 요소를 자세히 연구했으며 신경아교세포 형질전환의 효율성을 크게 높일 수 있는 적어도 세 가지 기술적 개선 사항을 발견했다.(1) VP16 융합 단백질의 삽입
VP16은 단순 헤르페스 바이러스(서열 번호 45)의 VP16 단백질의 활성 도메인이다. AAV-VP16-전사 인자/mCherry 플라스미드를 얻기 위해 유전자 서열을 AAV-전사 인자/mCherry 플라스미드로 복제했다. VP16은 단일 또는 다중 문자열일 수 있다. 플라스미드는 융합 단백질 VP16-전사 인자를 번역하여 전사 인자의 유전자 발현 활성화 기능을 강화한다. AAV-VP16-전사 인자/mCherry에 의해 유도된 뉴런의 효율은 상당히 더 높고 유도 속도는 더 빠르다(표 3 참조).
(2) 프로모터 쇼트닝
인간 hGFAP 프로모터 2.2kb(서열번호 42)를 683bp(서열번호 43)로 변경한 후, 우리는 수정된 프로모터가 표적 성상세포의 특이성에 영향을 미치지 않는 동시에 AAV의 패키징 효율을 개선하고 바이러스 패키징의 빈 껍질 비율을 감소시키며 더 높고 순수한 AAV 역가를 얻었다는 것을 발견했다. 생체 내에서 유도될 때 Short-hGFAP-AAV 전사 인자/mCherry는 바이러스 형질감염의 효율성을 개선하고 세포 사멸 횟수를 줄이며 유도 과정을 더 안전하게 만들 수 있다(표 3 참조).
(3) 인핸서 삽입
SV40-hGFAP-AAV 전사 인자/mCherry를 얻기 위해 유인원 액포형성 바이러스 40 SV40의 인핸서(서열 번호 46)를 hGFAP-AAV 전사 인자/mCherry 플라스미드에 삽입했다. SV40의 인핸서는 hGFAP 프로모터의 활성을 크게 향상시켜 표적 유전자가 생체 내에서 효율적으로 발현될 수 있도록 하여 뉴런 유도 효율을 향상시킬 수 있다(표 3 참조).
상기 3가지 발현 증진 방법은 단독으로 또는 조합하여 또는 동시에 사용할 수 있으며, 이는 본 실시예에 기재된 전사 인자의 유도 효율을 향상시킬 수 있다(인간 Ascl1을 예로 들면, 표 3 참조).
| 전사인자 | 서열목록 | VP16 삽입 | 프로모터 절단 |
SV40 삽입 |
| 야생형 hAscl1 | SEQ ID NO: 9 | 75.8% | 77.2% | 76.4% |
| 향상된 hAscl1 | SEQ ID NO: 41 | 88.4% | 89.2% | 88.9% |
유사하게, 다른 전사 인자의 경우, 위의 세 가지 기술 솔루션 중 하나가 변환 효율 또는 AAV 역가를 크게 향상시킬 수 있다. 표 4는 위의 변환 전략을 사용한 후 다른 전사 인자의 평균 변환 효율을 보여준다.
| 전사인자 | 서열목록 | VP16 삽입 | 프로모터 절단 |
SV40 삽입 |
| hNgn2 | SEQ ID NO: 13 | 73.8% | 74.2% | 74.4% |
| hNeuroD1 | SEQ ID NO: 1 | 68.3% | 69.6% | 68.5% |
| hDlx2 | SEQ ID NO: 25 | 25.3% | 26.3% | 25.4% |
전사 인자 조합은 신경아교세포 전환 분화의 효율을 향상시킬 수 있다
| 요소조합 | 표현 스케일 | 세포전환분화 50% 유도에 필요한 시간 (단위: 일) | 전분화 효율(계산방법은 실시예 1과 동일) | ||
| Factor A | Factor B | Factor A | Factor B | ||
| NeuroD1 | Brn2 | 1 | 1 | 11.2 | 76.2% |
| 2 | 1 | 13.6 | 71.5% | ||
| Gsx1 | Tbr1 | 1 | 1 | 12.4 | 63.2% |
| 2 | 1 | 14.7 | 56.9% | ||
| Dlx2 | Ptf1a | 1 | 1 | 11.7 | 69.2% |
| 3 | 1 | 12.8 | 61.2% | ||
| Pax6 | Otx2 | 1 | 1 | 12.3 | 63.8% |
| 2 | 1 | 13.9 | 54.3% | ||
NeuroD1과 Brn2를 예로 들면 단일 사용의 전환 분화 효율은 각각 42.30%와 8.70%였으며(표 1) 병용 사용(1:1)의 전환 분화 효율은 76.2%로 상승 효과가 있었다. 마찬가지로 Gsx1+Tbr1, Dlx2+Ptf1a, Pax6+Otx2도 전환 분화의 효율성을 상승적으로 크게 향상시킬 수 있다.연구에서 우리는 또한 Ascl1과 Ngn2가 두 가지 주요 전사 인자임을 발견했다. 상기 전사 인자 또는 전사 인자와 조합하면 전사 효율의 현저한 향상을 달성할 수 있고, 중첩 또는 상승 작용을 달성할 수 있다(표 6 및 7 참조).
| 주요오소 | 요소조합 | 표현 스케일 | 전분화 효율(계산방법은 실시예 1과 동일) | |||
| Factor A | Factor B | Factor C | Factor A | Factor B | Factor C | |
| Ascl1 | NeuroD1 | / | 1 | 4 | / | 82.2% |
| / | Brn2 | 1 | / | 2 | 81.5% | |
| NeuroD1 | Brn2 | 1 | 2 | 2 | 83.6% | |
| NeuroD1 | Brn2 | 1 | 1 | 1 | 83.7% | |
| NeuroD1 | Brn2 | 2 | 1 | 1 | 85.8% | |
| Ascl1 | Gsx1 | / | 1 | 1 | / | 81.5% |
| / | Tbr1 | 2 | / | 1 | 80.2% | |
| Gsx1 | Tbr1 | 2 | 1 | 1 | 83.5% | |
| Ascl1 | Dlx2 | / | 4 | 1 | / | 82.8% |
| / | Ptf1a | 2 | / | 1 | 81.4% | |
| Dlx2 | Ptf1a | 1 | 1 | 1 | 84.2% | |
| Ascl1 | Pax6 | / | 1 | 1 | / | 78.5% |
| / | Otx2 | 1 | / | 2 | 76.8% | |
| Pax6 | Otx2 | 1 | 2 | 2 | 80.3% | |
| Ascl1 | Ngn2 | / | 1 | 1 | / | 91.5% |
| Ngn2 | / | 4 | 1 | / | 86.3% | |
| Ngn2 | / | 1 | 4 | / | 85.4% | |
| 주요오소 | 요소조합 | 표현 스케일 | 전분화 효율(계산방법은 실시예 1과 동일) | |||
| Factor A | Factor B | Factor C | Factor A | Factor B | Factor C | |
| Ngn2 | NeuroD1 | / | 1 | 4 | / | 78.5% |
| NeuroD1 | / | 1 | 1 | / | 88.6% | |
| NeuroD1 | / | 4 | 1 | / | 75.6% | |
| / | Brn2 | 1 | / | 2 | 79.6% | |
| NeuroD1 | Brn2 | 1 | 2 | 2 | 82.3% | |
| NeuroD1 | Brn2 | 1 | 1 | 1 | 85.4% | |
| NeuroD1 | Brn2 | 2 | 1 | 1 | 88.2% | |
| Ngn2 | Gsx1 | / | 1 | 1 | / | 76.3% |
| / | Tbr1 | 2 | / | 1 | 77.9% | |
| Gsx1 | Tbr1 | 2 | 1 | 1 | 80.3% | |
| Ngn2 | Dlx2 | / | 4 | 1 | / | 75.4% |
| / | Ptf1a | 2 | / | 1 | 76.3% | |
| Dlx2 | Ptf1a | 1 | 1 | 1 | 79.8% | |
| Ngn2 | Pax6 | / | 1 | 1 | / | 75.1% |
| / | Otx2 | 1 | / | 2 | 76.3% | |
| Pax6 | Otx2 | 1 | 2 | 2 | 77.8% | |
Ac실시예 4 척수 손상 복구에 있어서 전사 인자 및 그의 조합의 적용척수 손상(SCI)은 일종의 중추신경계 손상 질환으로, 척수 뉴런의 사멸과 신경교 흉터 형성을 동반한다. In vivo 신경세포 재프로그래밍은 성상세포를 신경세포로 전환시켜 척수손상으로 인한 손상을 완화할 수 있어 새로운 치료법이 될 것으로 기대된다.
신경 손상 복구 모델에 따르면, 전환 효율이 50% 이상인 실시예 1-3에 기술된 전사 인자 또는 전사 인자의 조합이 손상 부위에서 신경아교세포를 유도하여 전기생리학적 특성을 얻는 능력을 가지고 있음을 발견하였고, 외부 신호 입력을 받아들일 수 있었다. 척수 손상의 탐지 모델에 따르면. 우리는 이러한 전사 인자 재프로그래밍 뉴런이 척수 손상 마우스의 감각 기능 및 운동 기능 회복에 매우 도움이 된다는 것을 발견했으며, 특히 실시예 1-3에서 설명한 전사 인자 또는 전사 인자의 조합은 전환 효율이 75% 이상인 것으로 나타났다 . 바람직한 전사 인자 및 이들의 조합은 표 8에 제시되어 있다.
| 주요요인 | 요인조합 | 표현 스케일 | |||
| Factor A | Factor B | Factor C | Factor A | Factor B | Factor C |
| Ascl1 | / | / | 1 | / | / |
| Ngn2 | / | 1 | 1 | / | |
| Dlx2 | Ptf1a | 1 | 1 | 1 | |
| Dlx2 | / | 2 | 1 | / | |
| NeuroD1 | / | 2 | 1 | / | |
| Ngn2 | / | / | 1 | / | / |
| NeuroD1 | Brn2 | 1 | 1 | 1 | |
| NeuroD1 | / | 1 | 1 | / | |
| / | NeuroD1 | Brn2 | / | 1 | 1 |
실시예 5 시험관내 신경아교종 세포에서 전사 인자 전환분화의 뉴런으로의 기능적 단편의 조합실시예 1-3과 같은 전사인자 및 이들의 조합을 얻은 것을 바탕으로 신경교종 세포의 신경세포로의 전환분화를 촉진하기 위해 전환 효율이 높은 전사인자 또는 전사인자의 조합을 적용하는 방법도 탐색하였다. 구현 계획은 생체 내 또는 시험관 내 교모세포 전환 분화 모델과 유사합니다. NeuroD1과 Brn2의 요소 조합을 예로 들면 구체적인 구현은 다음과 같다.
(1) 플라스미드 구축 및 바이러스 감염
렌티바이러스는 플레이트 배양 24시간 후 인간 신경아교종 세포에 첨가되었고, 배양 배지는 감염 24시간 후 DMEM/F12, B27, 글루타맥스 및 페니실린/스트렙토마이신으로 변경되었다. 감염 6-7일 후, 뇌유래신경영양인자(BDNF; PeproTech, 20ng/ml)를 3일마다 배양액에 첨가하였다.
(2) NeuroD1은 신경아교종 세포를 뉴런으로 변환한다.
배양된 인간 신경아교종 세포 U251에 hNeuroD1-IRES-EGFP 렌티바이러스를 14일 동안 감염시킨 후, 우리는 Tuj1 양성 세포의 일부가 나타나고 뉴런의 형태를 보여줌을 발견했다(도 1B, D). 이는 NeuroD1 단독으로 5.1%의 변환 효율로 신경교종 세포 U251을 뉴런으로 변환할 수 있음을 나타낸다.
(3) NeuroD1과 Brn2의 공동발현은 신경교종 세포가 뉴런으로 분화하는 효율을 향상시킨다. NeuroD1만으로도 신경아교종 세포를 뉴런으로 전환시킬 수 있지만 유도 효율은 그다지 높지 않다. 유도 효율을 향상시키기 위해 다른 전사 인자를 테스트한 결과, NeuroD1과 Brn2(서열 번호 7)가 함께 신경아교종 세포 U251을 매우 효율적으로 뉴런으로 변형시킬 수 있으며, 세포는 성숙한 뉴런의 형태를 보였다(도 1b). 1C, D) 변환 효율은 58.3%였다. 우리는 또한 다른 인간 신경아교종 세포 U87을 테스트했으며 NeuroD1과 Brn2가 신경아교종 세포 U87을 61.5%의 전환 효율로 매우 효율적으로 뉴런으로 변환할 수 있음을 발견했다.
(4) 신경교종 세포 전환분화 뉴런의 분자 발현 특성
신경아교종 세포 U251을 렌티바이러스 hNeuroD1-IRES-EGFP 및 hBrn2-IRES-EGFP로 감염시킨 지 21일 후, 세포 면역형광법은 유도된 뉴런이 마커 분자 MAP2 (도 2A) 및 성숙한 뉴런의 시냅신 I(도 2B-D)를 발현하고, 글루타메이트 뉴런의 마커 분자 VGLUT1(도 2E-H)을 발현하여 유도된 뉴런이 주로 흥분성 뉴런임을 나타낸다.
(5) 신경아교종 전환분화 뉴런의 전기생리학적 특성
신경아교종 세포 U251을 렌티바이러스 hNeuroD1-IRES-EGFP 및 hBrn2-IRES-EGFP로 28일 동안 감염시킨 후, 전기생리학적 기록은 유도된 뉴런이 다중 활동 전위를 방출할 수 있음을 보여주었다(도 3A, B). 그리고 유도된 뉴런의 시냅스 후 전류 신호를 감지할 수 있었다(도 3C). 차단제 CNQX와 AP5를 추가한 후, 시냅스 후 전류 신호가 사라졌는데, 이는 유도된 뉴런이 시냅스 신호를 받을 수 있고 기능적인 뉴런임을 나타냅니다.
(6) NeuroD1 및 Brn2 유도 전환 분화로 인해 신경아교종 세포가 세포 주기에서 철수됨
(7) NeuroD1 및 Brn2 유도 전환 분화는 신경교종 세포의 증식의 억제.
나아가, 증식세포인 내인성 분자마커 Ki67에 면역형광염색을 시행한 결과, NeuroD1과 Brn2 렌티바이러스에 의해 발현되는 Ki67 양성 신경아교종 세포의 수가 현저히 감소함을 확인하였다(도 5A, B). 우리는 서로 다른 시간 동안 바이러스 감염 후 세포 수에 대한 정량적 통계를 만들었고 NeuroD1 및 Brn2 lentivirus에 감염된 신경교종 세포의 성장이 7일째에 안정 상태에 도달했으며 더 이상 크게 증가하지 않음을 발견하였다(도 5C).
이러한 결과는 함께 NeuroD1 및 Brn2가 악성 증식성 신경교종 세포를 최종적으로 분화된 뉴런으로 유도할 수 있고, 신경교종 세포가 세포 주기에서 물러나서 더 이상 증식하지 않도록 할 수 있음을 보여준다.
(8) NeuroD1 및 Brn2를 발현하는 신경아교종 세포의 종양형성은 생체 내에서 상당히 감소되었다
NeuroD1 및 Brn2는 시험관 내에서 배양된 신경교종 세포를 뉴런으로 유도할 수 있고 신경교종 세포가 세포 주기에서 물러나게 할 수 있기 때문에 이러한 유도된 신경교종 세포가 생체 내에서 종양을 생성하는 능력도 영향을 받는다. 우리는 in situ 종양 세포 이식 실험을 수행했다. NeuroD1 및 Brn2 렌티바이러스로 3일 동안 감염된 인간 신경아교종 세포 U251 세포(5 × 105)를 NOD-scid 마우스의 선조체에 이식하고, 21일 후에 종양 조직 부피의 크기를 평가하였다. 결과는 대조군에 비해 NeuroD1 및 Brn2 렌티바이러스에 감염된 신경교종 세포의 종양 조직이 현저히 작았고, 이는 이들 신경교종 세포의 종양형성이 현저하게 감소했음을 나타낸다.
그런 다음, 신경아교종 세포에서 이들 전사인자 그룹의 분화전환 능력 및 신경아교종 세포의 증식 억제 능력을 테스트하기 위해 50% 이상의 형질전환 효율을 갖는 전사 인자 또는 전사 인자의 조합을 선택하고, 75% 이상의 전환 분화 효율을 갖는 전사 인자 또는 전사 인자의 조합이 교모세포 유래 종양에 대해 가장 우수한 억제 효과를 갖는다는 것을 발견하였다. 바람직한 전사 인자 및 이들의 조합은 표 9에 제시되어 있다.
| 주요요인 | 요인조합 | 표현 스케일 | |||
| Factor A | Factor B | Factor C | Factor A | Factor B | Factor C |
| Ascl1 | / | / | 1 | / | / |
| Ngn2 | / | 1 | 1 | / | |
| NeuroD1 | Brn2 | 1 | 1 | 1 | |
| Dlx2 | / | 2 | 1 | / | |
| NeuroD1 | / | 2 | 1 | / | |
| Ngn2 | / | / | 1 | / | / |
| Gsx1 | Tbr1 | 1 | 1 | 1 | |
| NeuroD1 | / | 1 | 1 | / | |
| / | NeuroD1 | Brn2 | / | 1 | 1 |
실시예 6 전사 인자 기능성 단편의 조합은 생체내 재프로그래밍을 통해 뇌에서 신경아교종 세포의 성장을 억제한다실시예 5에 기초하여, 우리는 여전히 NeuroD1과 Brn2의 조합을 예로 들어, 마우스 이식된 종양 모델에 대한 전사 인자의 효과를 검증하려고 시도하였고, 구체적인 구현은 다음과 같다:
(1) AAV 플라스미드의 제작
AAV-FLEX-Arch-GFP(Addgene, #22222)의 벡터 템플릿에서 인간 NeuroD1(SEQ ID No.: 3)의 단편을 벡터에 구성하여 AAV-hNeuroD1-P2A-GFP를 얻었다. P2A는 hNeuroD1과 GFP의 높은 동시 발현을 달성할 수 있는 자가 절단 폴리펩타이드이다. AAV-hBrn2-P2A-GFP를 얻기 위해 인간 Brn2 유전자로부터의 CDS(SEQ ID No.: 7) 단편을 벡터 상에 구축하였다.
(2) NeuroD1 및 Brn2의 AAV 벡터는 뇌에서 신경아교종 세포의 성장을 억제한다.
NeuroD1 및 Brn2 유도된 리프로그래밍이 신경교종 세포를 치료할 수 있는지 확인하기 위해 먼저 신경교종 세포(5×105개)의 뇌내 이식을 수행했다. 이식 7일 후, 우리는 NeuroD1과 Brn2의 AAV 벡터를 in situ로 주입했다. 바이러스 주입 30일 후, 면역조직화학 분석 결과, 바이러스에 감염된 세포는 신경 마커 분자인 Tuj1을 발현하여 뉴런의 형태를 보였다. 동시에 종양의 부피도 크게 감소했다. 더 중요한 것은 NeuroD1 및 Brn2 AAV 바이러스를 주사한 마우스의 수명이 상당히 연장되었다는 것이다.
75%보다 높은 전환 분화 효율을 갖는 다른 전사 인자 또는 전사 인자의 조합이 또한 신경아교종 억제 모델에서 관찰되었다.
(3) NeuroD1 및 Brn2를 발현하는 AAV 벡터는 인간 신경아교종 U87 BALB/CA-nu 마우스 이소성 접종 모델에서 종양 세포의 성장을 억제한다
배양된 인간 U87 인간 신경아교종 세포를 대수 성장기 동안 누드 마우스의 겨드랑이에 접종하고 2계대를 통과시켰다. 종양이 있는 마우스를 무균 상태에서 채취하여 종양을 균일한 크기의 작은 쌀알 조각으로 자르고 삽입 바늘로 누드 마우스의 겨드랑이에 피하 접종했다. 종양이 약 100mm3 정도로 자란 후 적당한 종양이 있는 누드마우스를 무작위로 그룹으로 나누고 그룹핑 후 약물투여를 시작하였다. 모든 샘플은 PBS로 용해하였고, 종양내 주사량은 50 μL/종양이었고, 3일마다 종양의 길이와 폭을 측정하고, 다음 공식으로 종양 부피를 계산하였다:
부피=(길이 × 폭2)/2
종양 억제율은 다음 공식에 따라 계산된다.
종양억제율% = (V 모델군 - V 투여군)/V 모델군 × 100%
이후 단계에서 동물을 죽였고, 생화학적 및 분자적 검출을 위해 종양의 무게를 쟀다. 결과는 AAV-매개 리프로그래밍 인자의 발현이 종양 부피를 상당히 감소시켰음을 보여주었다(도 6A). 종양 샘플의 실시간 PCR 분석 결과, 실험군의 세포가 초기 신경 마커 분자인 DCX를 발현하는 것으로 나타났으며(도 6B), 이는 동물 체내의 신경교종 세포가 뉴런이 되도록 유도되어 종양 성장이 억제됨을 나타낸다.
실시예 7 전사 인자의 기능적 단편 전달에 있어서 다른 전달 시스템의 적용
상기 실시예에서 설명한 렌티바이러스 벡터 및 아데노 관련 바이러스 벡터 이외에 다른 유형의 전달 시스템도 유사한 기능을 달성할 수 있다. 이 실시예에서, NeuroD1 및 Brn2를 발현하는 아데노바이러스 벡터 유형 5는 또한 인간 신경아교종 U87 BALB/CA-nu 마우스 이종 이식 모델 종양 세포의 성장을 억제할 수 있다.
아데노 관련 바이러스는 생체 내에서 독립적으로 복제할 수 없기 때문에 우리는 리프로그래밍 인자를 효율적이고 빠르게 발현하기 위해 아데노바이러스 5형 벡터를 설계했습니다. 종양 세포에서 아데노바이러스 5형의 특이적 증폭으로 우리는 신경아교종의 재발을 제어하기 위한 생체 내 전환 분화 요법의 효과를 달성할 수 있습니다.
Adeno-Cas9의 벡터 템플릿 (Addgene, # 64072)에는 인간 NeuroD1 (SEQ ID No .: 3) 및 인간 Brn2 유전자에서 유래된 CDS (SEQ ID No .: 7) 조각이 Age I / Spe I 이중 제한 부위를 통해 벡터에 구축되어 Ad5-hNeuroD1-P2A-hBrn2 (Ad5-AN)을 얻었습니다.
우리는 인간 신경아교종 U87 BALB/CA-nu 마우스의 이소성 접종 모델을 사용했습니다. 대수성장기에서 배양된 U87 인간 신경아교종 세포를 누드 마우스의 겨드랑이에 접종하고, 종양이 약 100mm3 정도로 성장했을 때 적절한 종양 덩어리를 가진 누드 마우스를 무작위로 그룹으로 나누고, 이후 약물을 투여하였다. 그룹화. 대조군은 PBS군이었고, Ad5-AN-low군은 3×108PFU Ad5-vector-high군은 1×109PFU로 2일에 1회씩 연속 5회 투여하였다. 3일마다 종양의 부피를 측정하여 계산하였으며, 후기 단계에서 동물을 도살하고 생화학적 및 분자적 검출을 위해 종양의 무게를 쟀다.
결과는 대조 PBS 그룹과 비교하여 Ad5-AN-낮은 그룹의 종양 부피가 32.25% 감소하고 Ad5-AN-높은 그룹의 종양 부피가 67.49% 감소함을 보여주었다(도 7A). 신경아교종의 재프로그래밍이 종양 세포의 성장을 상당히 감소시킨다는 것을 알 수 있다. HE 염색은 또한 신경아교종의 성장이 억제됨을 발견하였다(도 7B). 이러한 결과는 생체 내 재프로그래밍 인자-매개 신경아교종 전환 분화가 종양 세포 성장 억제를 유도함을 시사한다.
중간엽 세포나 교모세포종 세포에서 유래한 엑소좀(GBM-Exo)도 사용하였다. 밀도 구배 원심분리 및 분자 배제 분리에 의해 세포 배양 상등액으로부터 엑소좀을 추출하였고,
엑소좀 마커 단백질 CD63의 발현은 Western blot으로 확인하였고, 엑소좀의 형태 특성 및 입자 크기는 투과전자현미경과 동적광산란으로 검출하였고, 엑소좀의 농도는 BCA 단백질 정량법으로 검출하였다.
교모세포종의 경우, Ascl1-mRNA(NCBI 참조 서열: NM_004316.4) 또는 본 발명에 기재된 다른 전사 인자 조합이 내인성 발현 또는 외인성 도입을 통해 외분비체에 도입된다. 교모세포종에서 파생된 외분비 약물은 특히 인간 교모세포종 세포주 U251 및 U87을 감염시킨다. 세포의 대수 성장기에서 인간 교모세포종 세포주 U251 및 U87을 뉴런으로 유도하는 외분비 약물의 효율이 외분비 약물의 농도 구배에 따라 변할 수 있음을 관찰할 수 있으며, 관련 종양 세포 증식률은 또한 뉴런 유도 효율에 비례한다.
본 발명에 언급된 모든 문헌은 각각의 문헌이 참고문헌으로 별도로 인용되는 것과 마찬가지로 본 출원에서도 참고문헌으로 인용된다. 또한, 위의 발명의 설명을 읽은 후 당업자는 발명에 대해 다양한 변경 또는 수정을 가할 수 있으며, 이러한 균등한 형태도 출원서에 첨부된 특허청구범위에 속하는 것으로 이해되어야 한다.
<110> NEURAGEN BIOTHERAPEUTICS (SUZHOU) CO., LTD.
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Gly Leu Pro Ser Pro Pro Tyr Gly Thr Met Asp Ser Ser His Val Phe
225 230 235 240
His Val Lys Pro Pro Pro His Ala Tyr Ser Ala Ala Leu Glu Pro Phe
245 250 255
Phe Glu Ser Pro Leu Thr Asp Cys Thr Ser Pro Ser Phe Asp Gly Pro
260 265 270
Leu Ser Pro Pro Leu Ser Ile Asn Gly Asn Phe Ser Phe Lys His Glu
275 280 285
Pro Ser Ala Glu Phe Glu Lys Asn Tyr Ala Phe Thr Met His Tyr Pro
290 295 300
Ala Ala Thr Leu Ala Gly Pro Gln Ser His Gly Ser Ile Phe Ser Ser
305 310 315 320
Gly Ala Ala Ala Pro Arg Cys Glu Ile Pro Ile Asp Asn Ile Met Ser
325 330 335
Phe Asp Ser His Ser His His Glu Arg Val Met Ser Ala Gln Leu Asn
340 345 350
Ala Ile Phe His Asp
355
<210> 3
<211> 1071
<212> DNA
<213> Artificial Sequence
<220>
<223> Artificail Sequence
<400> 3
atgaccaaat cgtacagcga gagtgggctg atgggcgagc ctcagcccca aggtcctcca 60
agctggacag acgagtgtct cagttctcag gacgaggagc acgaggcaga caagaaggag 120
gacgacctcg aaaccatgaa cgcagaggag gactcactga ggaacggggg agaggaggag 180
gacgaagatg aggacctgga agaggaggaa gaagaggaag aggaggatga cgatcaaaag 240
cccaagagac gcggccccaa aaagaagaag atgactaagg ctcgcctgga gcgttttaaa 300
ttgagacgca tgaaggctaa cgcccgggag cggaaccgca tgcacggact gaacgcggcg 360
ctagacaacc tgcgcaaggt ggtgccttgc tattctaaga cgcagaagct gtccaaaatc 420
gagactctgc gcttggccaa gaactacatc tgggctctgt cggagatcct gcgctcaggc 480
aaaagcccag acctggtctc cttcgttcag acgctttgca agggcttatc ccaacccacc 540
accaacctgg ttgcgggctg cctgcaactc aatcctcgga cttttctgcc tgagcagaac 600
caggacatgc ccccccacct gccgacggcc agcgcttcct tccctgtaca cccctactcc 660
taccagtcgc ctgggctgcc cagtccgcct tacggtacca tggacagctc ccatgtcttc 720
cacgttaagc ctccgccgca cgcctacagc gcagcgctgg agcccttctt tgaaagccct 780
ctgactgatt gcaccagccc ttcctttgat ggacccctca gcccgccgct cagcatcaat 840
ggcaacttct ctttcaaaca cgaaccgtcc gccgagtttg agaaaaatta tgcctttacc 900
atgcactatc ctgcagcgac actggcaggg gcccaaagcc acggatcaat cttctcaggc 960
accgctgccc ctcgctgcga gatccccata gacaatatta tgtccttcga tagccattca 1020
catcatgagc gagtcatgag tgcccagctc aatgccatat ttcatgatta g 1071
<210> 4
<211> 1074
<212> DNA
<213> Artificial Sequence
<220>
<223> Artificail Sequence
<400> 4
atgaccaaat catacagcga gagcgggctg atgggcgagc ctcagcccca aggtccccca 60
agctggacag atgagtgtct cagttctcag gacgaggaac acgaggcaga caagaaagag 120
gacgagcttg aagccatgaa tgcagaggag gactctctga gaaacggggg agaggaggag 180
gaggaagatg aggatctaga ggaagaggag gaagaagaag aggaggagga ggatcaaaag 240
cccaagagac ggggtcccaa aaagaaaaag atgaccaagg cgcgcctaga acgttttaaa 300
ttaaggcgca tgaaggccaa cgcccgcgag cggaaccgca tgcacgggct gaacgcggcg 360
ctggacaacc tgcgcaaggt ggtaccttgc tactccaaga cccagaaact gtctaaaata 420
gagacactgc gcttggccaa gaactacatc tgggctctgt cagagatcct gcgctcaggc 480
aaaagccctg atctggtctc cttcgtacag acgctctgca aaggtttgtc ccagcccact 540
accaatttgg tcgccggctg cctgcagctc aaccctcgga ctttcttgcc tgagcagaac 600
ccggacatgc ccccgcatct gccaaccgcc agcgcttcct tcccggtgca tccctactcc 660
taccagtccc ctggactgcc cagcccgccc tacggcacca tggacagctc ccacgtcttc 720
cacgtcaagc cgccgccaca cgcctacagc gcagctctgg agcccttctt tgaaagcccc 780
ctaactgact gcaccagccc ttcctttgac ggacccctca gcccgccgct cagcatcaat 840
ggcaacttct ctttcaaaca cgaaccatcc gccgagtttg aaaaaaatta tgcctttacc 900
atgcactacc ctgcagcgac gctggcaggg ccccaaagcc acggatcaat cttctcttcc 960
ggtgccgctg cccctcgctg cgagatcccc atagacaaca ttatgtcttt cgatagccat 1020
tcgcatcatg agcgagtcat gagtgcccag cttaatgcca tctttcacga ttag 1074
<210> 5
<211> 443
<212> PRT
<213> Artificial Sequence
<220>
<223> Artificail Sequence
<400> 5
Met Ala Thr Ala Ala Ser Asn His Tyr Ser Leu Leu Thr Ser Ser Ala
1 5 10 15
Ser Ile Val His Ala Glu Pro Pro Gly Gly Met Gln Gln Gly Ala Gly
20 25 30
Gly Tyr Arg Glu Ala Gln Ser Leu Val Gln Gly Asp Tyr Gly Ala Leu
35 40 45
Gln Ser Asn Gly His Pro Leu Ser His Ala His Gln Trp Ile Thr Ala
50 55 60
Leu Ser His Gly Gly Gly Gly Gly Gly Gly Gly Gly Gly Gly Gly Gly
65 70 75 80
Gly Gly Gly Gly Gly Gly Gly Gly Asp Gly Ser Pro Trp Ser Thr Ser
85 90 95
Pro Leu Gly Gln Pro Asp Ile Lys Pro Ser Val Val Val Gln Gln Gly
100 105 110
Gly Arg Gly Asp Glu Leu His Gly Pro Gly Ala Leu Gln Gln Gln His
115 120 125
Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln
130 135 140
Gln Gln Gln Gln Gln Arg Pro Pro His Leu Val His His Ala Ala Asn
145 150 155 160
His His Pro Gly Pro Gly Ala Trp Arg Ser Ala Ala Ala Ala Ala His
165 170 175
Leu Pro Pro Ser Met Gly Ala Ser Asn Gly Gly Leu Leu Tyr Ser Gln
180 185 190
Pro Ser Phe Thr Val Asn Gly Met Leu Gly Ala Gly Gly Gln Pro Ala
195 200 205
Gly Leu His His His Gly Leu Arg Asp Ala His Asp Glu Pro His His
210 215 220
Ala Asp His His Pro His Pro His Ser His Pro His Gln Gln Pro Pro
225 230 235 240
Pro Pro Pro Pro Pro Gln Gly Pro Pro Gly His Pro Gly Ala His His
245 250 255
Asp Pro His Ser Asp Glu Asp Thr Pro Thr Ser Asp Asp Leu Glu Gln
260 265 270
Phe Ala Lys Gln Phe Lys Gln Arg Arg Ile Lys Leu Gly Phe Thr Gln
275 280 285
Ala Asp Val Gly Leu Ala Leu Gly Thr Leu Tyr Gly Asn Val Phe Ser
290 295 300
Gln Thr Thr Ile Cys Arg Phe Glu Ala Leu Gln Leu Ser Phe Lys Asn
305 310 315 320
Met Cys Lys Leu Lys Pro Leu Leu Asn Lys Trp Leu Glu Glu Ala Asp
325 330 335
Ser Ser Ser Gly Ser Pro Thr Ser Ile Asp Lys Ile Ala Ala Gln Gly
340 345 350
Arg Lys Arg Lys Lys Arg Thr Ser Ile Glu Val Ser Val Lys Gly Ala
355 360 365
Leu Glu Ser His Phe Leu Lys Cys Pro Lys Pro Ser Ala Gln Glu Ile
370 375 380
Thr Ser Leu Ala Asp Ser Leu Gln Leu Glu Lys Glu Val Val Arg Val
385 390 395 400
Trp Phe Cys Asn Arg Arg Gln Lys Glu Lys Arg Met Thr Pro Pro Gly
405 410 415
Gly Thr Leu Pro Gly Ala Glu Asp Val Tyr Gly Gly Ser Arg Asp Thr
420 425 430
Pro Pro His His Gly Val Gln Thr Pro Val Gln
435 440
<210> 6
<211> 445
<212> PRT
<213> Artificial Sequence
<220>
<223> Artificail Sequence
<400> 6
Met Ala Thr Ala Ala Ser Asn His Tyr Ser Leu Leu Thr Ser Ser Ala
1 5 10 15
Ser Ile Val His Ala Glu Pro Pro Gly Gly Met Gln Gln Gly Ala Gly
20 25 30
Gly Tyr Arg Glu Ala Gln Ser Leu Val Gln Gly Asp Tyr Gly Ala Leu
35 40 45
Gln Ser Asn Gly His Pro Leu Ser His Ala His Gln Trp Ile Thr Ala
50 55 60
Leu Ser His Gly Gly Gly Gly Gly Gly Gly Gly Gly Gly Gly Gly Gly
65 70 75 80
Gly Gly Gly Gly Gly Gly Gly Gly Asp Gly Ser Pro Trp Ser Thr Ser
85 90 95
Pro Leu Gly Gln Pro Asp Ile Lys Pro Ser Val Val Val Gln Gln Gly
100 105 110
Gly Arg Gly Asp Glu Leu His Gly Pro Gly Ala Leu Gln Gln Gln His
115 120 125
Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln
130 135 140
Gln Gln Gln Gln Gln Gln Gln Arg Pro Pro His Leu Val His His Ala
145 150 155 160
Ala Asn His His Pro Gly Pro Gly Ala Trp Arg Ser Ala Ala Ala Ala
165 170 175
Ala His Leu Pro Pro Ser Met Gly Ala Ser Asn Gly Gly Leu Leu Tyr
180 185 190
Ser Gln Pro Ser Phe Thr Val Asn Gly Met Leu Gly Ala Gly Gly Gln
195 200 205
Pro Ala Gly Leu His His His Gly Leu Arg Asp Ala His Asp Glu Pro
210 215 220
His His Ala Asp His His Pro His Pro His Ser His Pro His Gln Gln
225 230 235 240
Pro Pro Pro Pro Pro Pro Pro Gln Gly Pro Pro Gly His Pro Gly Ala
245 250 255
His His Asp Pro His Ser Asp Glu Asp Thr Pro Thr Ser Asp Asp Leu
260 265 270
Glu Gln Phe Ala Lys Gln Phe Lys Gln Arg Arg Ile Lys Leu Gly Phe
275 280 285
Thr Gln Ala Asp Val Gly Leu Ala Leu Gly Thr Leu Tyr Gly Asn Val
290 295 300
Phe Ser Gln Thr Thr Ile Cys Arg Phe Glu Ala Leu Gln Leu Ser Phe
305 310 315 320
Lys Asn Met Cys Lys Leu Lys Pro Leu Leu Asn Lys Trp Leu Glu Glu
325 330 335
Ala Asp Ser Ser Ser Gly Ser Pro Thr Ser Ile Asp Lys Ile Ala Ala
340 345 350
Gln Gly Arg Lys Arg Lys Lys Arg Thr Ser Ile Glu Val Ser Val Lys
355 360 365
Gly Ala Leu Glu Ser His Phe Leu Lys Cys Pro Lys Pro Ser Ala Gln
370 375 380
Glu Ile Thr Ser Leu Ala Asp Ser Leu Gln Leu Glu Lys Glu Val Val
385 390 395 400
Arg Val Trp Phe Cys Asn Arg Arg Gln Lys Glu Lys Arg Met Thr Pro
405 410 415
Pro Gly Gly Thr Leu Pro Gly Ala Glu Asp Val Tyr Gly Gly Ser Arg
420 425 430
Asp Thr Pro Pro His His Gly Val Gln Thr Pro Val Gln
435 440 445
<210> 7
<211> 1332
<212> DNA
<213> Artificial Sequence
<220>
<223> Artificail Sequence
<400> 7
atggcgaccg cagcgtctaa ccactacagc ctgctcacct ccagcgcctc catcgtgcac 60
gccgagccgc ccggcggcat gcagcagggc gcggggggct accgcgaagc gcagagcctg 120
gtgcagggcg actacggcgc tctgcagagc aacggacacc cgctcagcca cgctcaccag 180
tggatcaccg cgctgtccca cggcggcggc ggcgggggcg gtggcggcgg cggggggggc 240
gggggcggcg gcgggggcgg cggcgacggc tccccgtggt ccaccagccc cctgggccag 300
ccggacatca agccctcggt ggtggtgcag cagggcggcc gcggagacga gctgcacggg 360
ccaggcgccc tgcagcagca gcatcagcag cagcaacagc aacagcagca gcaacagcag 420
caacagcagc agcagcagca gcaacagcgg ccgccgcatc tggtgcacca cgccgctaac 480
caccacccgg gacccggggc atggcggagc gcggcggctg cagcgcacct cccaccctcc 540
atgggagcgt ccaacggcgg cttgctctac tcgcagccca gcttcacggt gaacggcatg 600
ctgggcgccg gcgggcagcc ggccggtctg caccaccacg gcctgcggga cgcgcacgac 660
gagccacacc atgccgacca ccacccgcac ccgcactcgc acccacacca gcagccgccg 720
cccccgccgc ccccgcaggg tccgcctggc cacccaggcg cgcaccacga cccgcactcg 780
gacgaggaca cgccgacctc ggacgacctg gagcagttcg ccaagcagtt caagcagcgg 840
cggatcaaac tgggatttac ccaagcggac gtggggctgg ctctgggcac cctgtatggc 900
aacgtgttct cgcagaccac catctgcagg tttgaggccc tgcagctgag cttcaagaac 960
atgtgcaagc tgaagccttt gttgaacaag tggttggagg aggcggactc gtcctcgggc 1020
agccccacga gcatagacaa gatcgcagcg caagggcgca agcggaaaaa gcggacctcc 1080
atcgaggtga gcgtcaaggg ggctctggag agccatttcc tcaaatgccc caagccctcg 1140
gcccaggaga tcacctccct cgcggacagc ttacagctgg agaaggaggt ggtgagagtt 1200
tggttttgta acaggagaca gaaagagaaa aggatgaccc ctcccggagg gactctgccg 1260
ggcgccgagg atgtgtacgg ggggagtagg gacactccac cacaccacgg ggtgcagacg 1320
cccgtccagt ga 1332
<210> 8
<211> 1338
<212> DNA
<213> Artificial Sequence
<220>
<223> Artificail Sequence
<400> 8
atggcgaccg cagcgtctaa ccactacagc ctgctcacct ccagcgcctc catcgtacat 60
gccgagccgc ctggcggcat gcagcagggc gcagggggct accgcgaggc gcagagcctg 120
gtgcagggcg actacggcgc gctgcagagc aacgggcacc cgctcagcca cgctcaccag 180
tggatcaccg cgctgtccca cggcggcggc ggcgggggcg gcggcggcgg tggaggaggc 240
gggggaggcg gcgggggagg cggcgacggc tccccgtggt ccaccagccc cctaggccag 300
ccggacatca agccctcggt ggtggtacag cagggtggcc gaggcgacga gctgcacggg 360
ccaggagcgc tgcagcaaca gcatcaacag caacagcaac agcagcagca gcagcagcag 420
cagcagcagc agcaacagca gcagcaacaa cagcgaccgc cacatctggt gcaccacgct 480
gccaaccacc atcccgggcc cggggcatgg cggagtgcgg cggctgcagc tcacctccct 540
ccctccatgg gagcttccaa cggcggtttg ctctattcgc agccgagctt cacggtgaac 600
ggcatgctgg gcgcaggagg gcagccggct gggctgcacc accacggcct gagggacgcc 660
cacgatgagc cacaccatgc agaccaccac ccgcatccgc actctcaccc acaccagcaa 720
ccgcccccgc cacctccccc acaaggccca ccgggccacc caggcgcgca ccacgacccg 780
cactcggacg aggacacgcc gacctcagac gacctggagc agttcgccaa gcaattcaag 840
cagaggcgga tcaaactcgg atttactcaa gcagacgtgg ggctggcgct tggcaccctg 900
tacggcaacg tgttctcgca gaccaccatc tgcaggtttg aggccctgca gctgagcttc 960
aagaacatgt gcaagctgaa gcctttgttg aacaagtggt tggaagaggc agactcatcc 1020
tcgggcagcc ccaccagcat agacaagatc gcagcgcaag ggcgcaaacg gaaaaagcgg 1080
acctccatcg aggtgagcgt caagggggct ctggagagcc atttcctcaa atgccctaag 1140
ccctcggccc aggagatcac ctccctcgcg gacagcttac agctggagaa ggaggtggtg 1200
agagtttggt tttgtaacag gagacagaaa gagaaaagga tgacccctcc cggagggact 1260
ctgccgggcg ccgaggatgt gtatgggggt agtagggaca cgccaccaca ccacggggtg 1320
cagacgcccg tccagtga 1338
<210> 9
<211> 236
<212> PRT
<213> Artificial Sequence
<220>
<223> Artificail Sequence
<400> 9
Met Glu Ser Ser Ala Lys Met Glu Ser Gly Gly Ala Gly Gln Gln Pro
1 5 10 15
Gln Pro Gln Pro Gln Gln Pro Phe Leu Pro Pro Ala Ala Cys Phe Phe
20 25 30
Ala Thr Ala Ala Ala Ala Ala Ala Ala Ala Ala Ala Ala Ala Ala Gln
35 40 45
Ser Ala Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Ala Pro
50 55 60
Gln Leu Arg Pro Ala Ala Asp Gly Gln Pro Ser Gly Gly Gly His Lys
65 70 75 80
Ser Ala Pro Lys Gln Val Lys Arg Gln Arg Ser Ser Ser Pro Glu Leu
85 90 95
Met Arg Cys Lys Arg Arg Leu Asn Phe Ser Gly Phe Gly Tyr Ser Leu
100 105 110
Pro Gln Gln Gln Pro Ala Ala Val Ala Arg Arg Asn Glu Arg Glu Arg
115 120 125
Asn Arg Val Lys Leu Val Asn Leu Gly Phe Ala Thr Leu Arg Glu His
130 135 140
Val Pro Asn Gly Ala Ala Asn Lys Lys Met Ser Lys Val Glu Thr Leu
145 150 155 160
Arg Ser Ala Val Glu Tyr Ile Arg Ala Leu Gln Gln Leu Leu Asp Glu
165 170 175
His Asp Ala Val Ser Ala Ala Phe Gln Ala Gly Val Leu Ser Pro Thr
180 185 190
Ile Ser Pro Asn Tyr Ser Asn Asp Leu Asn Ser Met Ala Gly Ser Pro
195 200 205
Val Ser Ser Tyr Ser Ser Asp Glu Gly Ser Tyr Asp Pro Leu Ser Pro
210 215 220
Glu Glu Gln Glu Leu Leu Asp Phe Thr Asn Trp Phe
225 230 235
<210> 10
<211> 231
<212> PRT
<213> Artificial Sequence
<220>
<223> Artificail Sequence
<400> 10
Met Glu Ser Ser Gly Lys Met Glu Ser Gly Ala Gly Gln Gln Pro Gln
1 5 10 15
Pro Pro Gln Pro Phe Leu Pro Pro Ala Ala Cys Phe Phe Ala Thr Ala
20 25 30
Ala Ala Ala Ala Ala Ala Ala Ala Ala Ala Ala Gln Ser Ala Gln Gln
35 40 45
Gln Gln Pro Gln Ala Pro Pro Gln Gln Ala Pro Gln Leu Ser Pro Val
50 55 60
Ala Asp Ser Gln Pro Ser Gly Gly Gly His Lys Ser Ala Ala Lys Gln
65 70 75 80
Val Lys Arg Gln Arg Ser Ser Ser Pro Glu Leu Met Arg Cys Lys Arg
85 90 95
Arg Leu Asn Phe Ser Gly Phe Gly Tyr Ser Leu Pro Gln Gln Gln Pro
100 105 110
Ala Ala Val Ala Arg Arg Asn Glu Arg Glu Arg Asn Arg Val Lys Leu
115 120 125
Val Asn Leu Gly Phe Ala Thr Leu Arg Glu His Val Pro Asn Gly Ala
130 135 140
Ala Asn Lys Lys Met Ser Lys Val Glu Thr Leu Arg Ser Ala Val Glu
145 150 155 160
Tyr Ile Arg Ala Leu Gln Gln Leu Leu Asp Glu His Asp Ala Val Ser
165 170 175
Ala Ala Phe Gln Ala Gly Val Leu Ser Pro Thr Ile Ser Pro Asn Tyr
180 185 190
Ser Asn Asp Leu Asn Ser Met Ala Gly Ser Pro Val Ser Ser Tyr Ser
195 200 205
Ser Asp Glu Gly Ser Tyr Asp Pro Leu Ser Pro Glu Glu Gln Glu Leu
210 215 220
Leu Asp Phe Thr Asn Trp Phe
225 230
<210> 11
<211> 711
<212> DNA
<213> Artificial Sequence
<220>
<223> Artificail Sequence
<400> 11
atggaaagct ctgccaagat ggagagcggc ggcgccggcc agcagcccca gccgcagccc 60
cagcagccct tcctgccgcc cgcagcctgt ttctttgcca cggccgcagc cgcggcggcc 120
gcagccgccg cagcggcagc gcagagcgcg cagcagcagc agcagcagca gcagcagcag 180
cagcaggcgc cgcagctgag accggcggcc gacggccagc cctcaggggg cggtcacaag 240
tcagcgccca agcaagtcaa gcgacagcgc tcgtcttcgc ccgaactgat gcgctgcaaa 300
cgccggctca acttcagcgg ctttggctac agcctgccgc agcagcagcc ggccgccgtg 360
gcgcgccgca acgagcgcga gcgcaaccgc gtcaagttgg tcaacctggg ctttgccacc 420
cttcgggagc acgtccccaa cggcgcggcc aacaagaaga tgagtaaggt ggagacactg 480
cgctcggcgg tcgagtacat ccgcgcgctg cagcagctgc tggacgagca tgacgcggtg 540
agcgccgcct tccaggcagg cgtcctgtcg cccaccatct cccccaacta ctccaacgac 600
ttgaactcca tggccggctc gccggtctca tcctactcgt cggacgaggg ctcttacgac 660
ccgctcagcc ccgaggagca ggagcttctc gacttcacca actggttctg a 711
<210> 12
<211> 696
<212> DNA
<213> Artificial Sequence
<220>
<223> Artificail Sequence
<400> 12
atggagagct ctggcaagat ggagagtgga gccggccagc agccgcagcc cccgcagccc 60
ttcctgcctc ccgcagcctg cttctttgcg accgcggcgg cggcggcagc ggcggcggcc 120
gcggcagctc agagcgcgca gcagcaacag ccgcaggcgc cgccgcagca ggcgccgcag 180
ctgagcccgg tggccgacag ccagccctca gggggcggtc acaagtcagc ggccaagcag 240
gtcaagcgcc agcgctcgtc ctctccggaa ctgatgcgct gcaaacgccg gctcaacttc 300
agcggcttcg gctacagcct gccacagcag cagccggccg ccgtggcgcg ccgcaacgag 360
cgcgagcgca accgggtcaa gttggtcaac ctgggttttg ccaccctccg ggagcatgtc 420
cccaacggcg cggccaacaa gaagatgagc aaggtggaga cgctgcgctc ggcggtcgag 480
tacatccgcg cgctgcagca gctgctggac gagcacgacg cggtgagcgc tgcctttcag 540
gcgggcgtcc tgtcgcccac catctccccc aactactcca acgacttgaa ctctatggcg 600
ggttctccgg tctcgtccta ctcctccgac gagggatcct acgaccctct tagcccagag 660
gaacaagagc tgctggactt taccaactgg ttctga 696
<210> 13
<211> 272
<212> PRT
<213> Artificial Sequence
<220>
<223> Artificail Sequence
<400> 13
Met Phe Val Lys Ser Glu Thr Leu Glu Leu Lys Glu Glu Glu Asp Val
1 5 10 15
Leu Val Leu Leu Gly Ser Ala Ser Pro Ala Leu Ala Ala Leu Thr Pro
20 25 30
Leu Ser Ser Ser Ala Asp Glu Glu Glu Glu Glu Glu Pro Gly Ala Ser
35 40 45
Gly Gly Ala Arg Arg Gln Arg Gly Ala Glu Ala Gly Gln Gly Ala Arg
50 55 60
Gly Gly Val Ala Ala Gly Ala Glu Gly Cys Arg Pro Ala Arg Leu Leu
65 70 75 80
Gly Leu Val His Asp Cys Lys Arg Arg Pro Ser Arg Ala Arg Ala Val
85 90 95
Ser Arg Gly Ala Lys Thr Ala Glu Thr Val Gln Arg Ile Lys Lys Thr
100 105 110
Arg Arg Leu Lys Ala Asn Asn Arg Glu Arg Asn Arg Met His Asn Leu
115 120 125
Asn Ala Ala Leu Asp Ala Leu Arg Glu Val Leu Pro Thr Phe Pro Glu
130 135 140
Asp Ala Lys Leu Thr Lys Ile Glu Thr Leu Arg Phe Ala His Asn Tyr
145 150 155 160
Ile Trp Ala Leu Thr Glu Thr Leu Arg Leu Ala Asp His Cys Gly Gly
165 170 175
Gly Gly Gly Gly Leu Pro Gly Ala Leu Phe Ser Glu Ala Val Leu Leu
180 185 190
Ser Pro Gly Gly Ala Ser Ala Ala Leu Ser Ser Ser Gly Asp Ser Pro
195 200 205
Ser Pro Ala Ser Thr Trp Ser Cys Thr Asn Ser Pro Ala Pro Ser Ser
210 215 220
Ser Val Ser Ser Asn Ser Thr Ser Pro Tyr Ser Cys Thr Leu Ser Pro
225 230 235 240
Ala Ser Pro Ala Gly Ser Asp Met Asp Tyr Trp Gln Pro Pro Pro Pro
245 250 255
Asp Lys His Arg Tyr Ala Pro His Leu Pro Ile Ala Arg Asp Cys Ile
260 265 270
<210> 14
<211> 263
<212> PRT
<213> Artificial Sequence
<220>
<223> Artificail Sequence
<400> 14
Met Phe Val Lys Ser Glu Thr Leu Glu Leu Lys Glu Glu Glu Glu Val
1 5 10 15
Leu Met Leu Leu Gly Ser Ala Ser Pro Ala Ser Ala Thr Leu Thr Pro
20 25 30
Met Ser Ser Ser Ala Asp Glu Glu Glu Asp Glu Glu Leu Arg Arg Pro
35 40 45
Gly Ser Ala Arg Gly Gln Arg Gly Ala Glu Ala Gly Gln Gly Val Gln
50 55 60
Gly Ser Pro Ala Ser Gly Ala Gly Gly Cys Arg Pro Gly Arg Leu Leu
65 70 75 80
Gly Leu Met His Glu Cys Lys Arg Arg Pro Ser Arg Ser Arg Ala Val
85 90 95
Ser Arg Gly Ala Lys Thr Ala Glu Thr Val Gln Arg Ile Lys Lys Thr
100 105 110
Arg Arg Leu Lys Ala Asn Asn Arg Glu Arg Asn Arg Met His Asn Leu
115 120 125
Asn Ala Ala Leu Asp Ala Leu Arg Glu Val Leu Pro Thr Phe Pro Glu
130 135 140
Asp Ala Lys Leu Thr Lys Ile Glu Thr Leu Arg Phe Ala His Asn Tyr
145 150 155 160
Ile Trp Ala Leu Thr Glu Thr Leu Arg Leu Ala Asp His Cys Ala Gly
165 170 175
Ala Gly Gly Leu Gln Gly Ala Leu Phe Thr Glu Ala Val Leu Leu Ser
180 185 190
Pro Gly Ala Ala Leu Gly Ala Ser Gly Asp Ser Pro Ser Pro Pro Ser
195 200 205
Ser Trp Ser Cys Thr Asn Ser Pro Ala Ser Ser Ser Asn Ser Thr Ser
210 215 220
Pro Tyr Ser Cys Thr Leu Ser Pro Ala Ser Pro Gly Ser Asp Val Asp
225 230 235 240
Tyr Trp Gln Pro Pro Pro Pro Glu Lys His Arg Tyr Ala Pro His Leu
245 250 255
Pro Leu Ala Arg Asp Cys Ile
260
<210> 15
<211> 819
<212> DNA
<213> Artificial Sequence
<220>
<223> Artificail Sequence
<400> 15
atgttcgtca aatccgagac cttggagttg aaggaggaag aggacgtgtt agtgctgctc 60
ggatcggcct cccccgcctt ggcggccctg accccgctgt catccagcgc cgacgaagaa 120
gaggaggagg agccgggcgc gtcaggcggg gcgcgtcggc agcgcggggc tgaggccggg 180
cagggggcgc ggggcggcgt ggctgcgggt gcggagggct gccggcccgc acggctgctg 240
ggtctggtac acgattgcaa acggcgccct tcccgggcgc gggccgtctc ccgaggcgcc 300
aagacggccg agacggtgca gcgcatcaag aagacccgta gactgaaggc caacaaccgc 360
gagcgaaacc gcatgcacaa cctcaacgcg gcactggacg cgctgcgcga ggtgctcccc 420
acgttccccg aggacgccaa gctcaccaag atcgagaccc tgcgcttcgc ccacaactac 480
atctgggcac tcaccgagac cctgcgcctg gcggatcact gcgggggcgg cggcgggggc 540
ctgccggggg cgctcttctc cgaggcagtg ttgctgagcc cgggaggagc cagcgccgcc 600
ctgagcagca gcggagacag cccctcgccc gcctccacgt ggagttgcac caacagcccc 660
gcgccgtcct cctccgtgtc ctccaattcc acctccccct acagctgcac tttatcgccc 720
gccagcccgg ccgggtcaga catggactat tggcagcccc cacctcccga caagcaccgc 780
tatgcacctc acctccccat agccagggat tgtatctag 819
<210> 16
<211> 792
<212> DNA
<213> Artificial Sequence
<220>
<223> Artificail Sequence
<400> 16
atgttcgtca aatctgagac tctggagttg aaggaggaag aggaggtact gatgctgctg 60
ggctcggctt ccccggcctc ggcgaccctg accccgatgt cctccagcgc ggacgaggag 120
gaggacgagg agctgcgccg gccgggctcc gcgcgtgggc agcgtggagc ggaagccggg 180
cagggggtgc agggcagtcc ggcgtcgggt gccgggggtt gccggccagg gcggctgctg 240
ggcctgatgc acgagtgcaa gcgtcgcccg tcgcgctcac gggccgtctc ccgaggtgcc 300
aagacggcgg agacggtgca gcgcatcaag aagacccgca ggctcaaggc caacaaccgc 360
gagcgcaacc gcatgcacaa cctaaacgcc gcgctggacg cgctgcgcga ggtgctgccc 420
accttccccg aggatgccaa gctcacgaag atcgagacgc tgcgcttcgc ccacaattac 480
atctgggcgc tcaccgagac tctgcgcctg gcggaccact gcgccggcgc cggtggcctc 540
cagggggcgc tcttcacgga ggcggtgctc ctgagcccgg gagctgcgct cggcgccagc 600
ggggacagcc cttctccacc ttcctcctgg agctgcacca acagcccggc gtcatcctcc 660
aactccacgt ccccatacag ctgcacttta tcgcccgcta gccccgggtc agacgtggac 720
tactggcagc ccccacctcc ggagaagcat cgttatgcgc ctcacctgcc cctcgccagg 780
gactgtatct ag 792
<210> 17
<211> 264
<212> PRT
<213> Artificial Sequence
<220>
<223> Artificail Sequence
<400> 17
Met Pro Arg Ser Phe Leu Val Asp Ser Leu Val Leu Arg Glu Ala Gly
1 5 10 15
Glu Lys Lys Ala Pro Glu Gly Ser Pro Pro Pro Leu Phe Pro Tyr Ala
20 25 30
Val Pro Pro Pro His Ala Leu His Gly Leu Ser Pro Gly Ala Cys His
35 40 45
Ala Arg Lys Ala Gly Leu Leu Cys Val Cys Pro Leu Cys Val Thr Ala
50 55 60
Ser Gln Leu His Gly Pro Pro Gly Pro Pro Ala Leu Pro Leu Leu Lys
65 70 75 80
Ala Ser Phe Pro Pro Phe Gly Ser Gln Tyr Cys His Ala Pro Leu Gly
85 90 95
Arg Gln His Ser Ala Val Ser Pro Gly Val Ala His Gly Pro Ala Ala
100 105 110
Ala Ala Ala Ala Ala Ala Leu Tyr Gln Thr Ser Tyr Pro Leu Pro Asp
115 120 125
Pro Arg Gln Phe His Cys Ile Ser Val Asp Ser Ser Ser Asn Gln Leu
130 135 140
Pro Ser Ser Lys Arg Met Arg Thr Ala Phe Thr Ser Thr Gln Leu Leu
145 150 155 160
Glu Leu Glu Arg Glu Phe Ala Ser Asn Met Tyr Leu Ser Arg Leu Arg
165 170 175
Arg Ile Glu Ile Ala Thr Tyr Leu Asn Leu Ser Glu Lys Gln Val Lys
180 185 190
Ile Trp Phe Gln Asn Arg Arg Val Lys His Lys Lys Glu Gly Lys Gly
195 200 205
Ser Asn His Arg Gly Gly Gly Gly Gly Gly Ala Gly Gly Gly Gly Ser
210 215 220
Ala Pro Gln Gly Cys Lys Cys Ala Ser Leu Ser Ser Ala Lys Cys Ser
225 230 235 240
Glu Asp Asp Asp Glu Leu Pro Met Ser Pro Ser Ser Ser Gly Lys Asp
245 250 255
Asp Arg Asp Leu Thr Val Thr Pro
260
<210> 18
<211> 261
<212> PRT
<213> Artificial Sequence
<220>
<223> Artificail Sequence
<400> 18
Met Pro Arg Ser Phe Leu Val Asp Ser Leu Val Leu Arg Glu Ala Ser
1 5 10 15
Asp Lys Lys Ala Pro Glu Gly Ser Pro Pro Pro Leu Phe Pro Tyr Ala
20 25 30
Val Pro Pro Pro His Ala Leu His Gly Leu Ser Pro Gly Ala Cys His
35 40 45
Ala Arg Lys Ala Gly Leu Leu Cys Val Cys Pro Leu Cys Val Thr Ala
50 55 60
Ser Gln Leu His Gly Pro Pro Gly Pro Pro Ala Leu Pro Leu Leu Lys
65 70 75 80
Ala Ser Phe Pro Pro Phe Gly Ser Gln Tyr Cys His Ala Pro Leu Gly
85 90 95
Arg Gln His Ser Val Ser Pro Gly Val Ala His Gly Pro Ala Ala Ala
100 105 110
Ala Ala Ala Ala Ala Leu Tyr Gln Thr Ser Tyr Pro Leu Pro Asp Pro
115 120 125
Arg Gln Phe His Cys Ile Ser Val Asp Ser Ser Ser Asn Gln Leu Pro
130 135 140
Ser Ser Lys Arg Met Arg Thr Ala Phe Thr Ser Thr Gln Leu Leu Glu
145 150 155 160
Leu Glu Arg Glu Phe Ala Ser Asn Met Tyr Leu Ser Arg Leu Arg Arg
165 170 175
Ile Glu Ile Ala Thr Tyr Leu Asn Leu Ser Glu Lys Gln Val Lys Ile
180 185 190
Trp Phe Gln Asn Arg Arg Val Lys His Lys Lys Glu Gly Lys Gly Ser
195 200 205
Asn His Arg Gly Gly Ala Gly Ala Gly Ala Gly Gly Gly Ala Pro Gln
210 215 220
Gly Cys Lys Cys Ser Ser Leu Ser Ser Ala Lys Cys Ser Glu Asp Asp
225 230 235 240
Asp Glu Leu Pro Met Ser Pro Ser Ser Ser Gly Lys Asp Asp Arg Asp
245 250 255
Leu Thr Val Thr Pro
260
<210> 19
<211> 795
<212> DNA
<213> Artificial Sequence
<220>
<223> Artificail Sequence
<400> 19
atgccgcgct ccttcctggt ggactcgcta gtgctgcgcg aggcgggcga gaagaaggcg 60
cccgagggca gcccgccgcc gctcttcccc tacgctgtgc ccccgccgca cgcgctgcac 120
ggtctctcgc ctggcgcctg ccacgcgcgc aaggctgggc tgctgtgcgt gtgcccgctc 180
tgcgtcaccg cctcgcagct gcatgggccc cccgggccgc ccgcgctgcc tctactcaag 240
gcttccttcc cacccttcgg ctcgcagtac tgccacgcgc ccctgggccg ccagcactct 300
gctgtgtcgc ccggggtcgc tcacggcccg gccgccgctg ctgctgccgc cgcgctctac 360
cagacctcct acccgctgcc tgaccccagg cagttccact gcatctctgt ggacagcagc 420
tctaaccagc tgcccagcag caagaggatg cgcacggctt tcaccagcac gcagctgcta 480
gagctggagc gcgagttcgc ttctaatatg tacctgtccc gcctacgtcg catcgagatc 540
gcgacctacc tgaatctgtc cgagaagcag gtgaagatct ggtttcagaa ccgccgagtg 600
aagcacaaga aggagggcaa gggcagcaac catcgtggcg gcggcggcgg gggtgccggt 660
ggtggcggga gcgcaccgca aggctgcaag tgcgcatcgc tctcctcagc caagtgctcc 720
gaggatgacg acgaattgcc catgtctccg tcctcctcag ggaaggacga ccgggatctt 780
acggtcactc cctag 795
<210> 20
<211> 786
<212> DNA
<213> Artificial Sequence
<220>
<223> Artificail Sequence
<400> 20
atgccgcgct ccttcctggt ggattccctt gtgctgcggg aagccagcga caagaaggct 60
ccggagggca gcccgccacc gctcttcccc tacgcggtcc cgccgccgca cgcgctccac 120
ggcctctcgc cgggcgcctg ccacgcgcgc aaggccggct tgctgtgcgt gtgtcccctc 180
tgtgtcaccg cttcgcagct gcacgggccc cccgggccgc cggcactgcc gctactcaag 240
gcgtccttcc ctcccttcgg atcgcagtac tgccacgcac ccctgggccg ccagcactcc 300
gtgtcccctg gagtcgccca cggcccggct gcggccgcag cagctgctgc actctaccag 360
acctcctacc cgctgccgga tcccagacag tttcactgca tctctgtgga cagcagctcg 420
aaccagctgc ccagcagcaa gaggatgcgg acggcgttca ccagcacaca gctcctggag 480
ctggagcgag agttcgcctc caacatgtac ctctcccgcc tgcggcgcat cgagatcgcg 540
acctatctga acctgtccga gaagcaggtg aagatctggt ttcagaaccg ccgggtgaag 600
cacaagaaag aaggcaaagg cagtaaccac cgcggcggag ctggggcggg ggccggcggg 660
ggcgcaccgc aaggctgcaa gtgctcttcg ctctcctcag ccaaatgctc agaggacgac 720
gacgaattgc ccatgtctcc atcttcctcc gggaaggatg acagagatct cacagtcact 780
ccgtag 786
<210> 21
<211> 682
<212> PRT
<213> Artificial Sequence
<220>
<223> Artificail Sequence
<400> 21
Met Gln Leu Glu His Cys Leu Ser Pro Ser Ile Met Leu Ser Lys Lys
1 5 10 15
Phe Leu Asn Val Ser Ser Ser Tyr Pro His Ser Gly Gly Ser Glu Leu
20 25 30
Val Leu His Asp His Pro Ile Ile Ser Thr Thr Asp Asn Leu Glu Arg
35 40 45
Ser Ser Pro Leu Lys Lys Ile Thr Arg Gly Met Thr Asn Gln Ser Asp
50 55 60
Thr Asp Asn Phe Pro Asp Ser Lys Asp Ser Pro Gly Asp Val Gln Arg
65 70 75 80
Ser Lys Leu Ser Pro Val Leu Asp Gly Val Ser Glu Leu Arg His Ser
85 90 95
Phe Asp Gly Ser Ala Ala Asp Arg Tyr Leu Leu Ser Gln Ser Ser Gln
100 105 110
Pro Gln Ser Ala Ala Thr Ala Pro Ser Ala Met Phe Pro Tyr Pro Gly
115 120 125
Gln His Gly Pro Ala His Pro Ala Phe Ser Ile Gly Ser Pro Ser Arg
130 135 140
Tyr Met Ala His His Pro Val Ile Thr Asn Gly Ala Tyr Asn Ser Leu
145 150 155 160
Leu Ser Asn Ser Ser Pro Gln Gly Tyr Pro Thr Ala Gly Tyr Pro Tyr
165 170 175
Pro Gln Gln Tyr Gly His Ser Tyr Gln Gly Ala Pro Phe Tyr Gln Phe
180 185 190
Ser Ser Thr Gln Pro Gly Leu Val Pro Gly Lys Ala Gln Val Tyr Leu
195 200 205
Cys Asn Arg Pro Leu Trp Leu Lys Phe His Arg His Gln Thr Glu Met
210 215 220
Ile Ile Thr Lys Gln Gly Arg Arg Met Phe Pro Phe Leu Ser Phe Asn
225 230 235 240
Ile Ser Gly Leu Asp Pro Thr Ala His Tyr Asn Ile Phe Val Asp Val
245 250 255
Ile Leu Ala Asp Pro Asn His Trp Arg Phe Gln Gly Gly Lys Trp Val
260 265 270
Pro Cys Gly Lys Ala Asp Thr Asn Val Gln Gly Asn Arg Val Tyr Met
275 280 285
His Pro Asp Ser Pro Asn Thr Gly Ala His Trp Met Arg Gln Glu Ile
290 295 300
Ser Phe Gly Lys Leu Lys Leu Thr Asn Asn Lys Gly Ala Ser Asn Asn
305 310 315 320
Asn Gly Gln Met Val Val Leu Gln Ser Leu His Lys Tyr Gln Pro Arg
325 330 335
Leu His Val Val Glu Val Asn Glu Asp Gly Thr Glu Asp Thr Ser Gln
340 345 350
Pro Gly Arg Val Gln Thr Phe Thr Phe Pro Glu Thr Gln Phe Ile Ala
355 360 365
Val Thr Ala Tyr Gln Asn Thr Asp Ile Thr Gln Leu Lys Ile Asp His
370 375 380
Asn Pro Phe Ala Lys Gly Phe Arg Asp Asn Tyr Asp Thr Ile Tyr Thr
385 390 395 400
Gly Cys Asp Met Asp Arg Leu Thr Pro Ser Pro Asn Asp Ser Pro Arg
405 410 415
Ser Gln Ile Val Pro Gly Ala Arg Tyr Ala Met Ala Gly Ser Phe Leu
420 425 430
Gln Asp Gln Phe Val Ser Asn Tyr Ala Lys Ala Arg Phe His Pro Gly
435 440 445
Ala Gly Ala Gly Pro Gly Pro Gly Thr Asp Arg Ser Val Pro His Thr
450 455 460
Asn Gly Leu Leu Ser Pro Gln Gln Ala Glu Asp Pro Gly Ala Pro Ser
465 470 475 480
Pro Gln Arg Trp Phe Val Thr Pro Ala Asn Asn Arg Leu Asp Phe Ala
485 490 495
Ala Ser Ala Tyr Asp Thr Ala Thr Asp Phe Ala Gly Asn Ala Ala Thr
500 505 510
Leu Leu Ser Tyr Ala Ala Ala Gly Val Lys Ala Leu Pro Leu Gln Ala
515 520 525
Ala Gly Cys Thr Gly Arg Pro Leu Gly Tyr Tyr Ala Asp Pro Ser Gly
530 535 540
Trp Gly Ala Arg Ser Pro Pro Gln Tyr Cys Gly Thr Lys Ser Gly Ser
545 550 555 560
Val Leu Pro Cys Trp Pro Asn Ser Ala Ala Ala Ala Ala Arg Met Ala
565 570 575
Gly Ala Asn Pro Tyr Leu Gly Glu Glu Ala Glu Gly Leu Ala Ala Glu
580 585 590
Arg Ser Pro Leu Pro Pro Gly Ala Ala Glu Asp Ala Lys Pro Lys Asp
595 600 605
Leu Ser Asp Ser Ser Trp Ile Glu Thr Pro Ser Ser Ile Lys Ser Ile
610 615 620
Asp Ser Ser Asp Ser Gly Ile Tyr Glu Gln Ala Lys Arg Arg Arg Ile
625 630 635 640
Ser Pro Ala Asp Thr Pro Val Ser Glu Ser Ser Ser Pro Leu Lys Ser
645 650 655
Glu Val Leu Ala Gln Arg Asp Cys Glu Lys Asn Cys Ala Lys Asp Ile
660 665 670
Ser Gly Tyr Tyr Gly Phe Tyr Ser His Ser
675 680
<210> 22
<211> 681
<212> PRT
<213> Artificial Sequence
<220>
<223> Artificail Sequence
<400> 22
Met Gln Leu Glu His Cys Leu Ser Pro Ser Ile Met Leu Ser Lys Lys
1 5 10 15
Phe Leu Asn Val Ser Ser Ser Tyr Pro His Ser Gly Gly Ser Glu Leu
20 25 30
Val Leu His Asp His Pro Ile Ile Ser Thr Thr Asp Asn Leu Glu Arg
35 40 45
Ser Ser Pro Leu Lys Lys Ile Thr Arg Gly Met Thr Asn Gln Ser Asp
50 55 60
Thr Asp Asn Phe Pro Asp Ser Lys Asp Ser Pro Gly Asp Val Gln Arg
65 70 75 80
Ser Lys Leu Ser Pro Val Leu Asp Gly Val Ser Glu Leu Arg His Ser
85 90 95
Phe Asp Gly Ser Ala Ala Asp Arg Tyr Leu Leu Ser Gln Ser Ser Gln
100 105 110
Pro Gln Ser Ala Ala Thr Ala Pro Ser Ala Met Phe Pro Tyr Pro Ser
115 120 125
Gln His Gly Pro Ala His Pro Ala Phe Ser Ile Gly Ser Pro Ser Arg
130 135 140
Tyr Met Ala His His Pro Val Ile Thr Asn Gly Ala Tyr Asn Ser Leu
145 150 155 160
Leu Ser Asn Ser Ser Pro Gln Gly Tyr Pro Thr Ala Gly Tyr Pro Tyr
165 170 175
Pro Gln Gln Tyr Gly His Ser Tyr Gln Gly Ala Pro Phe Tyr Gln Phe
180 185 190
Ser Ser Thr Gln Pro Gly Leu Val Pro Gly Lys Ala Gln Val Tyr Leu
195 200 205
Cys Asn Arg Pro Leu Trp Leu Lys Phe His Arg His Gln Thr Glu Met
210 215 220
Ile Ile Thr Lys Gln Gly Arg Arg Met Phe Pro Phe Leu Ser Phe Asn
225 230 235 240
Ile Ser Gly Leu Asp Pro Thr Ala His Tyr Asn Ile Phe Val Asp Val
245 250 255
Ile Leu Ala Asp Pro Asn His Trp Arg Phe Gln Gly Gly Lys Trp Val
260 265 270
Pro Cys Gly Lys Ala Asp Thr Asn Val Gln Gly Asn Arg Val Tyr Met
275 280 285
His Pro Asp Ser Pro Asn Thr Gly Ala His Trp Met Arg Gln Glu Ile
290 295 300
Ser Phe Gly Lys Leu Lys Leu Thr Asn Asn Lys Gly Ala Ser Asn Asn
305 310 315 320
Asn Gly Gln Met Val Val Leu Gln Ser Leu His Lys Tyr Gln Pro Arg
325 330 335
Leu His Val Val Glu Val Asn Glu Asp Gly Thr Glu Asp Thr Ser Gln
340 345 350
Pro Gly Arg Val Gln Thr Phe Thr Phe Pro Glu Thr Gln Phe Ile Ala
355 360 365
Val Thr Ala Tyr Gln Asn Thr Asp Ile Thr Gln Leu Lys Ile Asp His
370 375 380
Asn Pro Phe Ala Lys Gly Phe Arg Asp Asn Tyr Asp Thr Ile Tyr Thr
385 390 395 400
Gly Cys Asp Met Asp Arg Leu Thr Pro Ser Pro Asn Asp Ser Pro Arg
405 410 415
Ser Gln Ile Val Pro Gly Ala Arg Tyr Ala Met Ala Gly Ser Phe Leu
420 425 430
Gln Asp Gln Phe Val Ser Asn Tyr Ala Lys Ala Arg Phe His Pro Gly
435 440 445
Ala Gly Ala Gly Pro Gly Pro Gly Thr Asp Arg Ser Val Pro His Thr
450 455 460
Asn Gly Leu Leu Ser Pro Gln Gln Ala Glu Asp Pro Gly Ala Pro Ser
465 470 475 480
Pro Gln Arg Trp Phe Val Thr Pro Ala Asn Asn Arg Leu Asp Phe Ala
485 490 495
Ala Ser Ala Tyr Asp Thr Ala Thr Asp Phe Ala Gly Asn Ala Ala Thr
500 505 510
Leu Leu Ser Tyr Ala Ala Ala Gly Val Lys Ala Leu Pro Leu Gln Ala
515 520 525
Ala Gly Cys Thr Gly Arg Pro Leu Gly Tyr Tyr Ala Asp Pro Ser Gly
530 535 540
Trp Gly Ala Arg Ser Pro Pro Gln Tyr Cys Gly Ala Lys Ser Gly Ser
545 550 555 560
Val Leu Pro Cys Trp Pro Asn Ser Ala Ala Ala Ala Ala Arg Met Ala
565 570 575
Gly Ala Asn Pro Tyr Leu Gly Glu Glu Ala Glu Gly Leu Ala Ala Glu
580 585 590
Arg Ser Pro Leu Ala Pro Ala Ala Glu Asp Ala Lys Pro Lys Asp Leu
595 600 605
Ser Asp Ser Ser Trp Ile Glu Thr Pro Ser Ser Ile Lys Ser Ile Asp
610 615 620
Ser Ser Asp Ser Gly Ile Tyr Glu Gln Ala Lys Arg Arg Arg Ile Ser
625 630 635 640
Pro Ala Asp Thr Pro Val Ser Glu Ser Ser Ser Pro Leu Lys Ser Glu
645 650 655
Val Leu Ala Gln Arg Asp Cys Glu Lys Asn Cys Ala Lys Asp Ile Gly
660 665 670
Gly Tyr Tyr Gly Phe Tyr Ser His Ser
675 680
<210> 23
<211> 2049
<212> DNA
<213> Artificial Sequence
<220>
<223> Artificail Sequence
<400> 23
atgcagctgg agcactgcct ttctccttct atcatgctct ccaagaaatt tctcaatgtg 60
agcagcagct acccacattc aggcggatcc gagcttgtct tgcacgatca tcccattatc 120
tcgaccactg acaacctgga gagaagttca cctttgaaaa aaattaccag ggggatgacg 180
aatcagtcag atacagacaa ttttcctgac tccaaggact caccagggga cgtccagaga 240
agtaaactct ctcctgtctt ggacggggtc tctgagcttc gtcacagttt cgatggctct 300
gctgcagatc gctacctcct ctctcagtcc agccagccac agtctgcggc cactgctccc 360
agtgccatgt tcccgtaccc cggccagcac ggaccggcgc accccgcctt ctccatcggc 420
agccctagcc gctacatggc ccaccacccg gtcatcacca acggagccta caacagcctc 480
ctgtccaact cctcgccgca gggatacccc acggccggct acccctaccc acagcagtac 540
ggccactcct accaaggagc tccgttctac cagttctcct ccacccagcc ggggctggtg 600
cccggcaaag cacaggtgta cctgtgcaac aggccccttt ggctgaaatt tcaccggcac 660
caaacggaga tgatcatcac caaacaggga aggcgcatgt ttcctttttt aagttttaac 720
atttctggtc tcgatcccac ggctcattac aatatttttg tggatgtgat tttggcggat 780
cccaatcact ggaggtttca aggaggcaaa tgggttcctt gcggcaaagc ggacaccaat 840
gtgcaaggaa atcgggtcta tatgcatccg gattccccca acactggggc tcactggatg 900
cgccaagaaa tctcttttgg aaaattaaaa cttacgaaca acaaaggagc ttcaaataac 960
aatgggcaga tggtggtttt acagtccttg cacaagtacc agccccgcct gcatgtggtg 1020
gaagtgaacg aggacggcac ggaggacact agccagcccg gccgcgtgca gacgttcact 1080
ttccctgaga ctcagttcat cgccgtcacc gcctaccaga acacggatat tacacaactg 1140
aaaatagatc acaacccttt tgcaaaagga tttcgggata attatgacac gatctacacc 1200
ggctgtgaca tggaccgcct gaccccctcg cccaacgact cgccgcgctc gcagatcgtg 1260
cccggggccc gctacgccat ggccggctct ttcctgcagg accagttcgt gagcaactac 1320
gccaaggccc gcttccaccc gggcgcgggc gcgggccccg ggccgggtac ggaccgcagc 1380
gtgccgcaca ccaacgggct gctgtcgccg cagcaggccg aggacccggg cgcgccctcg 1440
ccgcaacgct ggtttgtgac gccggccaac aaccggctgg acttcgcggc ctcggcctat 1500
gacacggcca cggacttcgc gggcaacgcg gccacgctgc tctcttacgc ggcggcgggc 1560
gtgaaggcgc tgccgctgca ggctgcaggc tgcactggcc gcccgctcgg ctactacgcc 1620
gacccgtcgg gctggggcgc ccgcagtccc ccgcagtact gcggcaccaa gtcgggctcg 1680
gtgctgccct gctggcccaa cagcgccgcg gccgccgcgc gcatggccgg cgccaatccc 1740
tacctgggcg aggaggccga gggcctggcc gccgagcgct cgccgctgcc gcccggcgcc 1800
gccgaggacg ccaagcccaa ggacctgtcc gattccagct ggatcgagac gccctcctcg 1860
atcaagtcca tcgactccag cgactcgggg atttacgagc aggccaagcg gaggcggatc 1920
tcgccggccg acacgcccgt gtccgagagt tcgtccccgc tcaagagcga ggtgctggcc 1980
cagcgggact gcgagaagaa ctgcgccaag gacattagcg gctactatgg cttctactcg 2040
cacagctag 2049
<210> 24
<211> 2046
<212> DNA
<213> Artificial Sequence
<220>
<223> Artificail Sequence
<400> 24
atgcagctgg agcattgcct ctctccttct atcatgctct ccaagaaatt tctcaatgtg 60
agcagcagct acccacattc gggcggatct gagcttgtct tgcatgatca tcccattatc 120
tcgaccactg acaacctgga gagaagttca cctttgaaaa aaattaccag ggggatgacg 180
aatcagtcag atacagacaa ttttcctgac tccaaggact caccagggga cgtccagaga 240
agtaaactct ctcctgtctt ggacggggtc tctgagcttc gtcacagttt cgatggctct 300
gctgcagatc gttacctact ctctcagtcc agccagccac agtctgcggc caccgctccc 360
agtgccatgt tcccgtaccc cagccagcac ggaccggcgc atcccgcctt ctccatcggc 420
agccccagtc gctacatggc ccaccacccg gtcattacca acggagctta caacagcctg 480
ctgtccaact cttcgccgca gggctacccc acggccggct acccctaccc acagcagtac 540
ggccactcct accaaggagc ccctttctac cagttctcct ccacccagcc cgggttggtg 600
cccggcaagg cgcaagtata cctgtgcaac aggccacttt ggctgaaatt tcatcggcat 660
caaacggaga tgatcatcac taaacaggga aggcgcatgt ttcccttttt gagttttaac 720
atttctggtc tcgatcccac cgctcattac aatatttttg tggatgtgat tttggcggat 780
cccaatcact ggaggtttca aggaggcaaa tgggttcctt gtggcaaagc ggacaccaat 840
gtgcaaggaa accgggtcta tatgcatccg gattccccca acactggggc tcactggatg 900
cggcaagaaa tctcttttgg aaaattaaaa cttaccaaca acaagggagc atcaaacaac 960
aatgggcaga tggtggtttt acagtccctg cacaagtacc agccccgtct gcacgtggtg 1020
gaagtgaatg aggatggcac agaggacacc agccagccag gccgagtcca gacgttcact 1080
tttccggaga ctcagttcat cgctgtcacc gcctaccaga acacggatat tacacaacta 1140
aaaatagatc ataacccctt tgcaaaagga tttcgagata actatgacac gatctacacg 1200
ggctgcgaca tggaccgctt gaccccgtcg cccaacgact ctccgcgctc gcagatcgtg 1260
cccggcgccc gctacgccat ggccggctct ttcctgcaag accagttcgt gagcaactac 1320
gccaaggccc gcttccaccc gggcgccggc gcgggtcccg ggccgggcac ggaccgcagc 1380
gtgccgcaca ccaacgggct gctgtccccg cagcaggccg aggacccggg cgcgccgtcg 1440
ccgcagcgct ggttcgtcac gccggccaac aaccggctgg acttcgcggc ctcggcctac 1500
gacacggcca cggacttcgc cggcaacgcg gccacgctgc tgtcgtatgc ggccgcgggc 1560
gtgaaggcgc tgcccttgca ggccgcgggc tgcacgggcc gcccgctcgg ctactacgcc 1620
gacccttcgg gctggggcgc gcgcagcccc ccgcagtact gcggcgccaa gtcgggctcc 1680
gtgctcccct gctggcccaa cagcgccgcg gccgccgcgc gcatggccgg cgccaacccc 1740
tatctgggcg aggaggccga gggcctggcg gccgagcgct cgccgctggc gcccgccgcc 1800
gaggacgcca agcccaagga cctgtccgac tccagctgga tcgagacgcc ctcctccatc 1860
aaatccatcg actccagcga ctcggggatt tacgagcagg ccaagcggag gcggatctcg 1920
ccggctgaca cgccggtgtc tgagagctcg tccccgctca agagcgaggt gctggcccag 1980
cgggactgcg agaagaactg cgccaaggac ataggcggct actatggctt ctactcgcac 2040
agctag 2046
<210> 25
<211> 328
<212> PRT
<213> Artificial Sequence
<220>
<223> Artificail Sequence
<400> 25
Met Thr Gly Val Phe Asp Ser Leu Val Ala Asp Met His Ser Thr Gln
1 5 10 15
Ile Ala Ala Ser Ser Thr Tyr His Gln His Gln Gln Pro Pro Ser Gly
20 25 30
Gly Gly Ala Gly Pro Gly Gly Asn Ser Ser Ser Ser Ser Ser Leu His
35 40 45
Lys Pro Gln Glu Ser Pro Thr Leu Pro Val Ser Thr Ala Thr Asp Ser
50 55 60
Ser Tyr Tyr Thr Asn Gln Gln His Pro Ala Gly Gly Gly Gly Gly Gly
65 70 75 80
Gly Ser Pro Tyr Ala His Met Gly Ser Tyr Gln Tyr Gln Ala Ser Gly
85 90 95
Leu Asn Asn Val Pro Tyr Ser Ala Lys Ser Ser Tyr Asp Leu Gly Tyr
100 105 110
Thr Ala Ala Tyr Thr Ser Tyr Ala Pro Tyr Gly Thr Ser Ser Ser Pro
115 120 125
Ala Asn Asn Glu Pro Glu Lys Glu Asp Leu Glu Pro Glu Ile Arg Ile
130 135 140
Val Asn Gly Lys Pro Lys Lys Val Arg Lys Pro Arg Thr Ile Tyr Ser
145 150 155 160
Ser Phe Gln Leu Ala Ala Leu Gln Arg Arg Phe Gln Lys Thr Gln Tyr
165 170 175
Leu Ala Leu Pro Glu Arg Ala Glu Leu Ala Ala Ser Leu Gly Leu Thr
180 185 190
Gln Thr Gln Val Lys Ile Trp Phe Gln Asn Arg Arg Ser Lys Phe Lys
195 200 205
Lys Met Trp Lys Ser Gly Glu Ile Pro Ser Glu Gln His Pro Gly Ala
210 215 220
Ser Ala Ser Pro Pro Cys Ala Ser Pro Pro Val Ser Ala Pro Ala Ser
225 230 235 240
Trp Asp Phe Gly Val Pro Gln Arg Met Ala Gly Gly Gly Gly Pro Gly
245 250 255
Ser Gly Gly Ser Gly Ala Gly Ser Ser Gly Ser Ser Pro Ser Ser Ala
260 265 270
Ala Ser Ala Phe Leu Gly Asn Tyr Pro Trp Tyr His Gln Thr Ser Gly
275 280 285
Ser Ala Ser His Leu Gln Ala Thr Ala Pro Leu Leu His Pro Thr Gln
290 295 300
Thr Pro Gln Pro His His His His His His His Gly Gly Gly Gly Ala
305 310 315 320
Pro Val Ser Ala Gly Thr Ile Phe
325
<210> 26
<211> 332
<212> PRT
<213> Artificial Sequence
<220>
<223> Artificail Sequence
<400> 26
Met Thr Gly Val Phe Asp Ser Leu Val Ala Asp Met His Ser Thr Gln
1 5 10 15
Ile Thr Ala Ser Ser Thr Tyr His Gln His Gln Gln Pro Pro Ser Gly
20 25 30
Ala Gly Ala Gly Pro Gly Gly Asn Ser Asn Ser Ser Ser Ser Asn Ser
35 40 45
Ser Leu His Lys Pro Gln Glu Ser Pro Thr Leu Pro Val Ser Thr Ala
50 55 60
Thr Asp Ser Ser Tyr Tyr Thr Asn Gln Gln His Pro Ala Gly Gly Gly
65 70 75 80
Gly Gly Gly Ala Ser Pro Tyr Ala His Met Gly Ser Tyr Gln Tyr His
85 90 95
Ala Ser Gly Leu Asn Asn Val Ser Tyr Ser Ala Lys Ser Ser Tyr Asp
100 105 110
Leu Gly Tyr Thr Ala Ala Tyr Thr Ser Tyr Ala Pro Tyr Gly Thr Ser
115 120 125
Ser Ser Pro Val Asn Asn Glu Pro Asp Lys Glu Asp Leu Glu Pro Glu
130 135 140
Ile Arg Ile Val Asn Gly Lys Pro Lys Lys Val Arg Lys Pro Arg Thr
145 150 155 160
Ile Tyr Ser Ser Phe Gln Leu Ala Ala Leu Gln Arg Arg Phe Gln Lys
165 170 175
Thr Gln Tyr Leu Ala Leu Pro Glu Arg Ala Glu Leu Ala Ala Ser Leu
180 185 190
Gly Leu Thr Gln Thr Gln Val Lys Ile Trp Phe Gln Asn Arg Arg Ser
195 200 205
Lys Phe Lys Lys Met Trp Lys Ser Gly Glu Ile Pro Thr Glu Gln His
210 215 220
Pro Gly Ala Ser Ala Ser Pro Pro Cys Ala Ser Pro Pro Val Ser Ala
225 230 235 240
Pro Ala Ser Trp Asp Phe Gly Ala Pro Gln Arg Met Ala Gly Gly Gly
245 250 255
Pro Gly Ser Gly Gly Gly Gly Ala Gly Ser Ser Gly Ser Ser Pro Ser
260 265 270
Ser Ala Ala Ser Ala Phe Leu Gly Asn Tyr Pro Trp Tyr His Gln Ala
275 280 285
Ser Gly Ser Ala Ser His Leu Gln Ala Thr Ala Pro Leu Leu His Pro
290 295 300
Ser Gln Thr Pro Gln Ala His His His His His His His His His Ala
305 310 315 320
Gly Gly Gly Ala Pro Val Ser Ala Gly Thr Ile Phe
325 330
<210> 27
<211> 987
<212> DNA
<213> Artificial Sequence
<220>
<223> Artificail Sequence
<400> 27
atgactggag tctttgacag tctagtggct gatatgcact cgacccagat cgccgcctcc 60
agcacgtacc accagcacca gcagcccccg agcggcggcg gcgccggccc gggtggcaac 120
agcagcagca gcagcagcct ccacaagccc caggagtcgc ccacccttcc ggtgtccacc 180
gccaccgaca gcagctacta caccaaccag cagcacccgg cgggcggcgg cggcggcggg 240
ggctcgccct acgcgcacat gggttcctac cagtaccaag ccagcggcct caacaacgtc 300
ccttactccg ccaagagcag ctatgacctg ggctacaccg ccgcctacac ctcctacgct 360
ccctatggaa ccagttcgtc cccagccaac aacgagcctg agaaggagga ccttgagcct 420
gaaattcgga tagtgaacgg gaagccaaag aaagtccgga aaccccgcac catctactcc 480
agtttccagc tggcggctct tcagcggcgt ttccaaaaga ctcaatactt ggccttgccg 540
gagcgagccg agctggcggc ctctctgggc ctcacccaga ctcaggtcaa aatctggttc 600
cagaaccgcc ggtccaagtt caagaagatg tggaaaagtg gtgagatccc ctcggagcag 660
caccctgggg ccagcgcttc tccaccttgt gcttcgccgc cagtctcagc gccggcctcc 720
tgggactttg gtgtgccgca gcggatggcg ggcggcggtg gtccgggcag tggcggcagc 780
ggcgccggca gctcgggctc cagcccgagc agcgcggcct cggcttttct gggcaactac 840
ccctggtacc accagacctc gggatccgcc tcacacctgc aggccacggc gccgctgctg 900
caccccactc agaccccgca gccgcatcac caccaccacc atcacggcgg cgggggcgcc 960
ccggtgagcg cggggacgat tttctaa 987
<210> 28
<211> 999
<212> DNA
<213> Artificial Sequence
<220>
<223> Artificail Sequence
<400> 28
atgactggag tctttgacag tctggtggct gatatgcact cgacccagat caccgcctcc 60
agcacgtacc accagcacca gcagcccccg agcggtgcgg gcgccggccc tggcggcaac 120
agcaacagca gcagcagcaa cagcagcctg cacaagcccc aggagtcgcc aaccctcccg 180
gtgtccacgg ctacggacag cagctactac accaaccagc agcacccggc gggcggcggc 240
ggcggggggg cctcgcccta cgcgcacatg ggctcctacc agtaccacgc cagcggcctc 300
aacaatgtct cctactccgc caaaagcagc tacgacctgg gctacaccgc cgcgtacacc 360
tcctacgcgc cctacggcac cagttcgtct ccggtcaaca acgagccgga caaggaagac 420
cttgagcctg aaatccgaat agtgaacggg aagccaaaga aagtccggaa accacgcacc 480
atctactcca gtttccagct ggcggccctt caacgacgct tccagaagac ccagtatctg 540
gccctgccag agcgagccga gctggcggcg tccctgggcc tcacccaaac tcaggtcaaa 600
atctggttcc agaaccgccg atccaagttc aagaagatgt ggaaaagcgg cgagataccc 660
accgagcagc accctggagc cagcgcttct cctccttgtg cctccccgcc ggtctcggcg 720
ccagcatcct gggacttcgg cgcgccgcag cggatggctg gcggcggccc gggcagcgga 780
ggcggcggtg cgggcagctc tggctccagc ccgagcagcg ccgcctcggc ctttctggga 840
aactacccgt ggtaccacca ggcttcgggc tccgcttcac acctgcaggc cacagcgcca 900
cttctgcatc cttcgcagac tccgcaggcg caccatcacc accatcacca ccaccacgca 960
ggcgggggcg ccccggtgag cgcggggacg attttctaa 999
<210> 29
<211> 328
<212> PRT
<213> Artificial Sequence
<220>
<223> Artificail Sequence
<400> 29
Met Asp Ala Val Leu Leu Glu His Phe Pro Gly Gly Leu Asp Ala Phe
1 5 10 15
Pro Ser Ser Tyr Phe Asp Glu Asp Asp Phe Phe Thr Asp Gln Ser Ser
20 25 30
Arg Asp Pro Leu Glu Asp Gly Asp Glu Leu Leu Ala Asp Glu Gln Ala
35 40 45
Glu Val Glu Phe Leu Ser His Gln Leu His Glu Tyr Cys Tyr Arg Asp
50 55 60
Gly Ala Cys Leu Leu Leu Gln Pro Ala Pro Pro Ala Ala Pro Leu Ala
65 70 75 80
Leu Ala Pro Pro Ser Ser Gly Gly Leu Gly Glu Pro Asp Asp Gly Gly
85 90 95
Gly Gly Gly Tyr Cys Cys Glu Thr Gly Ala Pro Pro Gly Gly Phe Pro
100 105 110
Tyr Ser Pro Gly Ser Pro Pro Ser Cys Leu Ala Tyr Pro Cys Ala Gly
115 120 125
Ala Ala Val Leu Ser Pro Gly Ala Arg Leu Arg Gly Leu Ser Gly Ala
130 135 140
Ala Ala Ala Ala Ala Arg Arg Arg Arg Arg Val Arg Ser Glu Ala Glu
145 150 155 160
Leu Gln Gln Leu Arg Gln Ala Ala Asn Val Arg Glu Arg Arg Arg Met
165 170 175
Gln Ser Ile Asn Asp Ala Phe Glu Gly Leu Arg Ser His Ile Pro Thr
180 185 190
Leu Pro Tyr Glu Lys Arg Leu Ser Lys Val Asp Thr Leu Arg Leu Ala
195 200 205
Ile Gly Tyr Ile Asn Phe Leu Ser Glu Leu Val Gln Ala Asp Leu Pro
210 215 220
Leu Arg Gly Gly Gly Ala Gly Gly Cys Gly Gly Pro Gly Gly Gly Gly
225 230 235 240
Arg Leu Gly Gly Asp Ser Pro Gly Ser Gln Ala Gln Lys Val Ile Ile
245 250 255
Cys His Arg Gly Thr Arg Ser Pro Ser Pro Ser Asp Pro Asp Tyr Gly
260 265 270
Leu Pro Pro Leu Ala Gly His Ser Leu Ser Trp Thr Asp Glu Lys Gln
275 280 285
Leu Lys Glu Gln Asn Ile Ile Arg Thr Ala Lys Val Trp Thr Pro Glu
290 295 300
Asp Pro Arg Lys Leu Asn Ser Lys Ser Ser Phe Asn Asn Ile Glu Asn
305 310 315 320
Glu Pro Pro Phe Glu Phe Val Ser
325
<210> 30
<211> 324
<212> PRT
<213> Artificial Sequence
<220>
<223> Artificail Sequence
<400> 30
Met Asp Ala Val Leu Leu Glu His Phe Pro Gly Gly Leu Asp Thr Phe
1 5 10 15
Pro Ser Pro Tyr Phe Asp Glu Glu Asp Phe Phe Thr Asp Gln Ser Ser
20 25 30
Arg Asp Pro Leu Glu Asp Ser Asp Glu Leu Leu Gly Asp Glu Gln Ala
35 40 45
Glu Val Glu Phe Leu Ser His Gln Leu His Glu Tyr Cys Tyr Arg Asp
50 55 60
Gly Ala Cys Leu Leu Leu Gln Pro Ala Pro Ser Ala Ala Pro His Ala
65 70 75 80
Leu Ala Pro Pro Pro Leu Gly Asp Pro Gly Glu Pro Glu Asp Asn Val
85 90 95
Ser Tyr Cys Cys Asp Ala Gly Ala Pro Leu Ala Ala Phe Pro Tyr Ser
100 105 110
Pro Gly Ser Pro Pro Ser Cys Leu Ala Tyr Pro Cys Ala Ala Val Leu
115 120 125
Ser Pro Gly Ala Arg Leu Gly Gly Leu Asn Gly Ala Ala Ala Ala Ala
130 135 140
Ala Ala Arg Arg Arg Arg Arg Val Arg Ser Glu Ala Glu Leu Gln Gln
145 150 155 160
Leu Arg Gln Ala Ala Asn Val Arg Glu Arg Arg Arg Met Gln Ser Ile
165 170 175
Asn Asp Ala Phe Glu Gly Leu Arg Ser His Ile Pro Thr Leu Pro Tyr
180 185 190
Glu Lys Arg Leu Ser Lys Val Asp Thr Leu Arg Leu Ala Ile Gly Tyr
195 200 205
Ile Asn Phe Leu Ser Glu Leu Val Gln Ala Asp Leu Pro Leu Arg Gly
210 215 220
Ser Gly Ala Gly Gly Cys Gly Gly Pro Gly Gly Ser Arg His Leu Gly
225 230 235 240
Glu Asp Ser Pro Gly Asn Gln Ala Gln Lys Val Ile Ile Cys His Arg
245 250 255
Gly Thr Arg Ser Pro Ser Pro Ser Asp Pro Asp Tyr Gly Leu Pro Pro
260 265 270
Leu Ala Gly His Ser Leu Ser Trp Thr Asp Glu Lys Gln Leu Lys Glu
275 280 285
Gln Asn Ile Ile Arg Thr Ala Lys Val Trp Thr Pro Glu Asp Pro Arg
290 295 300
Lys Leu Asn Ser Lys Ser Phe Asp Asn Ile Glu Asn Glu Pro Pro Phe
305 310 315 320
Glu Phe Val Ser
<210> 31
<211> 987
<212> DNA
<213> Artificial Sequence
<220>
<223> Artificail Sequence
<400> 31
atggacgcgg tgttgctgga gcacttcccc gggggcctag acgcctttcc ttcttcgtac 60
ttcgacgagg acgacttctt caccgaccag tcttcacggg accccctgga ggacggcgat 120
gagctgctgg cggacgagca ggccgaggtg gagttcctta gccaccagct ccacgagtac 180
tgctaccgcg acggggcgtg cctgctgctg cagcccgcgc ccccggccgc cccgctagcg 240
ctcgccccgc cgtcctcggg gggcctcggt gagccagacg acggcggcgg cggcggctac 300
tgctgcgaga cgggggcgcc cccaggcggc ttcccctact cgcccggctc gccgccctcg 360
tgcctggcct acccgtgcgc cggggcggca gtactgtctc ccggggcgcg gctgcgcggc 420
ctgagcggag cggcggctgc ggcggcgcgg cgccggcggc gggtgcgctc cgaggcggag 480
ctgcagcagc tgcggcaggc ggccaacgtg cgcgagcggc ggcgcatgca gtccatcaac 540
gacgccttcg aggggctgcg ctcgcacatc cccacgctgc cctacgagaa gcgcctctcc 600
aaggtggaca cgctgcgcct ggccatcggc tacatcaact tcctcagcga gctcgtgcag 660
gccgacctgc ccttgcgcgg cggtggcgcg ggcggctgcg gggggccggg cggcggcggg 720
cgcctgggcg gggacagccc gggcagccag gcccagaagg tcatcatctg ccatcggggc 780
acccggtccc cctcccccag cgaccctgat tatggcctcc ctcccctagc aggacactct 840
ctctcatgga ctgatgaaaa acaactcaag gaacaaaata ttatccgaac agccaaagtc 900
tggaccccag aggaccccag aaaactcaac agcaaatctt ccttcaacaa catagaaaac 960
gaaccaccat ttgagtttgt gtcctga 987
<210> 32
<211> 975
<212> DNA
<213> Artificial Sequence
<220>
<223> Artificail Sequence
<400> 32
atggacgccg tactcctgga gcacttcccc gggggcctgg acaccttccc atccccttac 60
tttgatgagg aagatttctt caccgaccag tcctctcggg acccgctgga ggacagcgac 120
gagctgctgg gggacgagca agcagaagta gagttcctca gccaccagct acacgaatac 180
tgctaccgcg acggggcgtg cctgctgctg caacccgcgc cctcggccgc cccgcacgcg 240
ctcgccccgc cgcctttggg ggatcctggc gagcccgagg acaacgtcag ctattgctgc 300
gatgcagggg ctcctctcgc tgccttcccc tactcgcctg gctcaccgcc ctcgtgcctc 360
gcctacccgt gtgccgcggt gctgtccccc ggtgcgcggc tcggtggttt gaacggggct 420
gcggcagcgg cggcagcaag gcggcggcga cgcgtgcgct ccgaggcgga gctgcagcag 480
ctgcgacaag ccgctaatgt gcgagagcgg cgccgcatgc agtccatcaa cgacgccttc 540
gaggggctgc gttcgcacat ccccacgcta ccctacgaaa agcgcctctc caaagtagac 600
acgctgcgct tggccatagg ctacattaac ttcctcagcg agctggtgca agccgacctg 660
ccgctgcgcg ggagtggcgc aggtggttgc gggggcccag gtggcagccg gcacctcgga 720
gaggacagtc ccggtaacca ggcccagaag gttatcatct gccatcgagg cacccgttca 780
ccctccccca gtgacccgga ttatggtctc cctcctcttg cagggcactc tctttcctgg 840
actgatgaaa aacagctcaa agaacaaaat atcatccgta cagctaaagt gtggacccca 900
gaggacccca gaaaactcaa cagtaaatct ttcgacaaca tagagaacga accacccttt 960
gagtttgtgt cctga 975
<210> 33
<211> 422
<212> PRT
<213> Artificial Sequence
<220>
<223> Artificail Sequence
<400> 33
Met Gln Asn Ser His Ser Gly Val Asn Gln Leu Gly Gly Val Phe Val
1 5 10 15
Asn Gly Arg Pro Leu Pro Asp Ser Thr Arg Gln Lys Ile Val Glu Leu
20 25 30
Ala His Ser Gly Ala Arg Pro Cys Asp Ile Ser Arg Ile Leu Gln Val
35 40 45
Ser Asn Gly Cys Val Ser Lys Ile Leu Gly Arg Tyr Tyr Glu Thr Gly
50 55 60
Ser Ile Arg Pro Arg Ala Ile Gly Gly Ser Lys Pro Arg Val Ala Thr
65 70 75 80
Pro Glu Val Val Ser Lys Ile Ala Gln Tyr Lys Arg Glu Cys Pro Ser
85 90 95
Ile Phe Ala Trp Glu Ile Arg Asp Arg Leu Leu Ser Glu Gly Val Cys
100 105 110
Thr Asn Asp Asn Ile Pro Ser Val Ser Ser Ile Asn Arg Val Leu Arg
115 120 125
Asn Leu Ala Ser Glu Lys Gln Gln Met Gly Ala Asp Gly Met Tyr Asp
130 135 140
Lys Leu Arg Met Leu Asn Gly Gln Thr Gly Ser Trp Gly Thr Arg Pro
145 150 155 160
Gly Trp Tyr Pro Gly Thr Ser Val Pro Gly Gln Pro Thr Gln Asp Gly
165 170 175
Cys Gln Gln Gln Glu Gly Gly Gly Glu Asn Thr Asn Ser Ile Ser Ser
180 185 190
Asn Gly Glu Asp Ser Asp Glu Ala Gln Met Arg Leu Gln Leu Lys Arg
195 200 205
Lys Leu Gln Arg Asn Arg Thr Ser Phe Thr Gln Glu Gln Ile Glu Ala
210 215 220
Leu Glu Lys Glu Phe Glu Arg Thr His Tyr Pro Asp Val Phe Ala Arg
225 230 235 240
Glu Arg Leu Ala Ala Lys Ile Asp Leu Pro Glu Ala Arg Ile Gln Val
245 250 255
Trp Phe Ser Asn Arg Arg Ala Lys Trp Arg Arg Glu Glu Lys Leu Arg
260 265 270
Asn Gln Arg Arg Gln Ala Ser Asn Thr Pro Ser His Ile Pro Ile Ser
275 280 285
Ser Ser Phe Ser Thr Ser Val Tyr Gln Pro Ile Pro Gln Pro Thr Thr
290 295 300
Pro Val Ser Ser Phe Thr Ser Gly Ser Met Leu Gly Arg Thr Asp Thr
305 310 315 320
Ala Leu Thr Asn Thr Tyr Ser Ala Leu Pro Pro Met Pro Ser Phe Thr
325 330 335
Met Ala Asn Asn Leu Pro Met Gln Pro Pro Val Pro Ser Gln Thr Ser
340 345 350
Ser Tyr Ser Cys Met Leu Pro Thr Ser Pro Ser Val Asn Gly Arg Ser
355 360 365
Tyr Asp Thr Tyr Thr Pro Pro His Met Gln Thr His Met Asn Ser Gln
370 375 380
Pro Met Gly Thr Ser Gly Thr Thr Ser Thr Gly Leu Ile Ser Pro Gly
385 390 395 400
Val Ser Val Pro Val Gln Val Pro Gly Ser Glu Pro Asp Met Ser Gln
405 410 415
Tyr Trp Pro Arg Leu Gln
420
<210> 34
<211> 436
<212> PRT
<213> Artificial Sequence
<220>
<223> Artificail Sequence
<400> 34
Met Gln Asn Ser His Ser Gly Val Asn Gln Leu Gly Gly Val Phe Val
1 5 10 15
Asn Gly Arg Pro Leu Pro Asp Ser Thr Arg Gln Lys Ile Val Glu Leu
20 25 30
Ala His Ser Gly Ala Arg Pro Cys Asp Ile Ser Arg Ile Leu Gln Thr
35 40 45
His Ala Asp Ala Lys Val Gln Val Leu Asp Asn Glu Asn Val Ser Asn
50 55 60
Gly Cys Val Ser Lys Ile Leu Gly Arg Tyr Tyr Glu Thr Gly Ser Ile
65 70 75 80
Arg Pro Arg Ala Ile Gly Gly Ser Lys Pro Arg Val Ala Thr Pro Glu
85 90 95
Val Val Ser Lys Ile Ala Gln Tyr Lys Arg Glu Cys Pro Ser Ile Phe
100 105 110
Ala Trp Glu Ile Arg Asp Arg Leu Leu Ser Glu Gly Val Cys Thr Asn
115 120 125
Asp Asn Ile Pro Ser Val Ser Ser Ile Asn Arg Val Leu Arg Asn Leu
130 135 140
Ala Ser Glu Lys Gln Gln Met Gly Ala Asp Gly Met Tyr Asp Lys Leu
145 150 155 160
Arg Met Leu Asn Gly Gln Thr Gly Ser Trp Gly Thr Arg Pro Gly Trp
165 170 175
Tyr Pro Gly Thr Ser Val Pro Gly Gln Pro Thr Gln Asp Gly Cys Gln
180 185 190
Gln Gln Glu Gly Gly Gly Glu Asn Thr Asn Ser Ile Ser Ser Asn Gly
195 200 205
Glu Asp Ser Asp Glu Ala Gln Met Arg Leu Gln Leu Lys Arg Lys Leu
210 215 220
Gln Arg Asn Arg Thr Ser Phe Thr Gln Glu Gln Ile Glu Ala Leu Glu
225 230 235 240
Lys Glu Phe Glu Arg Thr His Tyr Pro Asp Val Phe Ala Arg Glu Arg
245 250 255
Leu Ala Ala Lys Ile Asp Leu Pro Glu Ala Arg Ile Gln Val Trp Phe
260 265 270
Ser Asn Arg Arg Ala Lys Trp Arg Arg Glu Glu Lys Leu Arg Asn Gln
275 280 285
Arg Arg Gln Ala Ser Asn Thr Pro Ser His Ile Pro Ile Ser Ser Ser
290 295 300
Phe Ser Thr Ser Val Tyr Gln Pro Ile Pro Gln Pro Thr Thr Pro Val
305 310 315 320
Ser Ser Phe Thr Ser Gly Ser Met Leu Gly Arg Thr Asp Thr Ala Leu
325 330 335
Thr Asn Thr Tyr Ser Ala Leu Pro Pro Met Pro Ser Phe Thr Met Ala
340 345 350
Asn Asn Leu Pro Met Gln Pro Pro Val Pro Ser Gln Thr Ser Ser Tyr
355 360 365
Ser Cys Met Leu Pro Thr Ser Pro Ser Val Asn Gly Arg Ser Tyr Asp
370 375 380
Thr Tyr Thr Pro Pro His Met Gln Thr His Met Asn Ser Gln Pro Met
385 390 395 400
Gly Thr Ser Gly Thr Thr Ser Thr Gly Leu Ile Ser Pro Gly Val Ser
405 410 415
Val Pro Val Gln Val Pro Gly Ser Glu Pro Asp Met Ser Gln Tyr Trp
420 425 430
Pro Arg Leu Gln
435
<210> 35
<211> 1269
<212> DNA
<213> Artificial Sequence
<220>
<223> Artificail Sequence
<400> 35
atgcagaaca gtcacagcgg agtgaatcag ctcggtggtg tctttgtcaa cgggcggcca 60
ctgccggact ccacccggca gaagattgta gagctagctc acagcggggc ccggccgtgc 120
gacatttccc gaattctgca ggtgtccaac ggatgtgtga gtaaaattct gggcaggtat 180
tacgagactg gctccatcag acccagggca atcggtggta gtaaaccgag agtagcgact 240
ccagaagttg taagcaaaat agcccagtat aagcgggagt gcccgtccat ctttgcttgg 300
gaaatccgag acagattact gtccgagggg gtctgtacca acgataacat accaagcgtg 360
tcatcaataa acagagttct tcgcaacctg gctagcgaaa agcaacagat gggcgcagac 420
ggcatgtatg ataaactaag gatgttgaac gggcagaccg gaagctgggg cacccgccct 480
ggttggtatc cggggacttc ggtgccaggg caacctacgc aagatggctg ccagcaacag 540
gaaggagggg gagagaatac caactccatc agttccaacg gagaagattc agatgaggct 600
caaatgcgac ttcagctgaa gcggaagctg caaagaaata gaacatcctt tacccaagag 660
caaattgagg ccctggagaa agagtttgag agaacccatt atccagatgt gtttgcccga 720
gaaagactag cagccaaaat agatctacct gaagcaagaa tacaggtatg gttttctaat 780
cgaagggcca aatggagaag agaagaaaaa ctgaggaatc agagaagaca ggccagcaac 840
acacctagtc atattcctat cagcagtagt ttcagcacca gtgtctacca accaattcca 900
caacccacca caccggtttc ctccttcaca tctggctcca tgttgggccg aacagacaca 960
gccctcacaa acacctacag cgctctgccg cctatgccca gcttcaccat ggcaaataac 1020
ctgcctatgc aacccccagt ccccagccag acctcctcat actcctgcat gctgcccacc 1080
agcccttcgg tgaatgggcg gagttatgat acctacaccc ccccacatat gcagacacac 1140
atgaacagtc agccaatggg cacctcgggc accacttcaa caggactcat ttcccctggt 1200
gtgtcagttc cagttcaagt tcccggaagt gaacctgata tgtctcaata ctggccaaga 1260
ttacagtaa 1269
<210> 36
<211> 1311
<212> DNA
<213> Artificial Sequence
<220>
<223> Artificail Sequence
<400> 36
atgcagaaca gtcacagcgg agtgaatcag cttggtggtg tctttgtcaa cgggcggcca 60
ctgccggact ccacccggca gaagatcgta gagctagctc acagcggggc ccggccgtgc 120
gacatttccc gaattctgca gacccatgca gatgcaaaag tccaggtgct ggacaatgaa 180
aacgtatcca acggttgtgt gagtaaaatt ctgggcaggt attacgagac tggctccatc 240
agacccaggg caatcggagg gagtaagcca agagtggcga ctccagaagt tgtaagcaaa 300
atagcccagt ataaacggga gtgcccttcc atctttgctt gggaaatccg agacagatta 360
ttatccgagg gggtctgtac caacgataac atacccagtg tgtcatcaat aaacagagtt 420
cttcgcaacc tggctagcga aaagcaacag atgggcgcag acggcatgta tgataaacta 480
aggatgttga acgggcagac cggaagctgg ggcacacgcc ctggttggta tcccgggact 540
tcagtaccag ggcaacccac gcaagatggc tgccagcaac aggaaggagg gggagagaac 600
accaactcca tcagttctaa cggagaagac tcggatgaag ctcagatgcg acttcagctg 660
aagcggaagc tgcaaagaaa tagaacatct tttacccaag agcagattga ggctctggag 720
aaagagtttg agaggaccca ttatccagat gtgtttgccc gggaaagact agcagccaaa 780
atagatctac ctgaagcaag aatacaggta tggttttcta atcgaagggc caaatggaga 840
agagaagaga aactgaggaa ccagagaaga caggccagca acactcctag tcacattcct 900
atcagcagca gcttcagtac cagtgtctac cagccaatcc cacagcccac cacacctgtc 960
tcctccttca catcaggttc catgttgggc cgaacagaca ccgccctcac caacacgtac 1020
agtgctttgc cacccatgcc cagcttcacc atggcaaaca acctgcctat gcaaccccca 1080
gtccccagtc agacctcctc atactcgtgc atgctgccca ccagcccgtc agtgaatggg 1140
cggagttatg atacctacac ccctccgcac atgcaaacac acatgaacag tcagcccatg 1200
ggcacctcgg ggaccacttc aacaggactc atttcacctg gagtgtcagt tcccgtccaa 1260
gttcccggga gtgaacctga catgtctcag tactggcctc gattacagta a 1311
<210> 37
<211> 289
<212> PRT
<213> Artificial Sequence
<220>
<223> Artificail Sequence
<400> 37
Met Met Ser Tyr Leu Lys Gln Pro Pro Tyr Ala Val Asn Gly Leu Ser
1 5 10 15
Leu Thr Thr Ser Gly Met Asp Leu Leu His Pro Ser Val Gly Tyr Pro
20 25 30
Ala Thr Pro Arg Lys Gln Arg Arg Glu Arg Thr Thr Phe Thr Arg Ala
35 40 45
Gln Leu Asp Val Leu Glu Ala Leu Phe Ala Lys Thr Arg Tyr Pro Asp
50 55 60
Ile Phe Met Arg Glu Glu Val Ala Leu Lys Ile Asn Leu Pro Glu Ser
65 70 75 80
Arg Val Gln Val Trp Phe Lys Asn Arg Arg Ala Lys Cys Arg Gln Gln
85 90 95
Gln Gln Gln Gln Gln Asn Gly Gly Gln Asn Lys Val Arg Pro Ala Lys
100 105 110
Lys Lys Thr Ser Pro Ala Arg Glu Val Ser Ser Glu Ser Gly Thr Ser
115 120 125
Gly Gln Phe Thr Pro Pro Ser Ser Thr Ser Val Pro Thr Ile Ala Ser
130 135 140
Ser Ser Ala Pro Val Ser Ile Trp Ser Pro Ala Ser Ile Ser Pro Leu
145 150 155 160
Ser Asp Pro Leu Ser Thr Ser Ser Ser Cys Met Gln Arg Ser Tyr Pro
165 170 175
Met Thr Tyr Thr Gln Ala Ser Gly Tyr Ser Gln Gly Tyr Ala Gly Ser
180 185 190
Thr Ser Tyr Phe Gly Gly Met Asp Cys Gly Ser Tyr Leu Thr Pro Met
195 200 205
His His Gln Leu Pro Gly Pro Gly Ala Thr Leu Ser Pro Met Gly Thr
210 215 220
Asn Ala Val Thr Ser His Leu Asn Gln Ser Pro Ala Ser Leu Ser Thr
225 230 235 240
Gln Gly Tyr Gly Ala Ser Ser Leu Gly Phe Asn Ser Thr Thr Asp Cys
245 250 255
Leu Asp Tyr Lys Asp Gln Thr Ala Ser Trp Lys Leu Asn Phe Asn Ala
260 265 270
Asp Cys Leu Asp Tyr Lys Asp Gln Thr Ser Ser Trp Lys Phe Gln Val
275 280 285
Leu
<210> 38
<211> 297
<212> PRT
<213> Artificial Sequence
<220>
<223> Artificail Sequence
<400> 38
Met Met Ser Tyr Leu Lys Gln Pro Pro Tyr Ala Val Asn Gly Leu Ser
1 5 10 15
Leu Thr Thr Ser Gly Met Asp Leu Leu His Pro Ser Val Gly Tyr Pro
20 25 30
Gly Pro Trp Ala Ser Cys Pro Ala Ala Thr Pro Arg Lys Gln Arg Arg
35 40 45
Glu Arg Thr Thr Phe Thr Arg Ala Gln Leu Asp Val Leu Glu Ala Leu
50 55 60
Phe Ala Lys Thr Arg Tyr Pro Asp Ile Phe Met Arg Glu Glu Val Ala
65 70 75 80
Leu Lys Ile Asn Leu Pro Glu Ser Arg Val Gln Val Trp Phe Lys Asn
85 90 95
Arg Arg Ala Lys Cys Arg Gln Gln Gln Gln Gln Gln Gln Asn Gly Gly
100 105 110
Gln Asn Lys Val Arg Pro Ala Lys Lys Lys Ser Ser Pro Ala Arg Glu
115 120 125
Val Ser Ser Glu Ser Gly Thr Ser Gly Gln Phe Ser Pro Pro Ser Ser
130 135 140
Thr Ser Val Pro Thr Ile Ala Ser Ser Ser Ala Pro Val Ser Ile Trp
145 150 155 160
Ser Pro Ala Ser Ile Ser Pro Leu Ser Asp Pro Leu Ser Thr Ser Ser
165 170 175
Ser Cys Met Gln Arg Ser Tyr Pro Met Thr Tyr Thr Gln Ala Ser Gly
180 185 190
Tyr Ser Gln Gly Tyr Ala Gly Ser Thr Ser Tyr Phe Gly Gly Met Asp
195 200 205
Cys Gly Ser Tyr Leu Thr Pro Met His His Gln Leu Pro Gly Pro Gly
210 215 220
Ala Thr Leu Ser Pro Met Gly Thr Asn Ala Val Thr Ser His Leu Asn
225 230 235 240
Gln Ser Pro Ala Ser Leu Ser Thr Gln Gly Tyr Gly Ala Ser Ser Leu
245 250 255
Gly Phe Asn Ser Thr Thr Asp Cys Leu Asp Tyr Lys Asp Gln Thr Ala
260 265 270
Ser Trp Lys Leu Asn Phe Asn Ala Asp Cys Leu Asp Tyr Lys Asp Gln
275 280 285
Thr Ser Ser Trp Lys Phe Gln Val Leu
290 295
<210> 39
<211> 870
<212> DNA
<213> Artificial Sequence
<220>
<223> Artificail Sequence
<400> 39
atgatgtctt atcttaagca accgccttac gcagtcaatg ggctgagtct gaccacttcg 60
ggtatggact tgctgcaccc ctccgtgggc tacccggcca ccccccggaa acagcgccgg 120
gagaggacga cgttcactcg ggcgcagcta gatgtgctgg aagcactgtt tgccaagacc 180
cggtacccag acatcttcat gcgagaggag gtggcactga aaatcaactt gcccgagtcg 240
agggtgcagg tatggtttaa gaatcgaaga gctaagtgcc gccaacaaca gcaacaacag 300
cagaatggag gtcaaaacaa agtgagacct gccaaaaaga agacatctcc agctcgggaa 360
gtgagttcag agagtggaac aagtggccaa ttcactcccc cctctagcac ctcagtcccg 420
accattgcca gcagcagtgc tcctgtgtct atctggagcc cagcttccat ctccccactg 480
tcagatccct tgtccacctc ctcttcctgc atgcagaggt cctatcccat gacctatact 540
caggcttcag gttatagtca aggatatgct ggctcaactt cctactttgg gggcatggac 600
tgtggatcat atttgacccc tatgcatcac cagcttcccg gaccaggggc cacactcagt 660
cccatgggta ccaatgcagt caccagccat ctcaatcagt ccccagcttc tctttccacc 720
cagggatatg gagcttcaag cttgggtttt aactcaacca ctgattgctt ggattataag 780
gaccaaactg cctcctggaa gcttaacttc aatgctgact gcttggatta taaagatcag 840
acatcctcgt ggaaattcca ggttttgtga 870
<210> 40
<211> 894
<212> DNA
<213> Artificial Sequence
<220>
<223> Artificail Sequence
<400> 40
atgatgtctt atctaaagca accgccttac gcagtcaatg ggctgagtct gaccacttcg 60
ggtatggact tgctgcatcc ctccgtgggc taccccgggc cctgggcttc ttgtcctgca 120
gccacccccc ggaaacagcg aagggagagg acgacattta ctagggcaca gctcgacgtt 180
ctggaagctc tgtttgccaa gacccggtac ccagacatct tcatgaggga agaggtggca 240
ctgaaaatca acttgccaga atccagggtg caggtatggt ttaagaatcg aagagctaag 300
tgccgccaac agcagcagca gcagcagaat ggaggtcaga acaaagtgag gcctgccaag 360
aagaagagct ctccagctcg ggaagtgagt tcagagagtg gaacaagtgg ccagttcagt 420
cccccctcta gtacctcagt cccaaccatt gccagcagca gtgctccagt gtctatctgg 480
agcccagcgt ccatctcccc actgtctgac cccttgtcca cttcctcctc ctgcatgcag 540
aggtcctatc ccatgaccta tactcaggct tcaggttata gtcaaggcta tgctggctca 600
acttcctact ttgggggcat ggactgtgga tcttatttga cccctatgca tcaccagctt 660
cctggaccag gggccacact cagtcccatg ggtaccaatg ctgttaccag ccatctcaat 720
cagtccccag cttctctttc cacccaggga tatggagctt caagcttggg ttttaactca 780
accactgatt gcttggatta taaggaccaa actgcctctt ggaagcttaa cttcaatgct 840
gactgcttgg attataaaga tcagacgtcc tcatggaaat tccaggtttt gtga 894
<210> 41
<211> 236
<212> PRT
<213> Artificial Sequence
<220>
<223> Artificail Sequence
<400> 41
Met Glu Ser Ser Ala Lys Met Glu Ser Gly Gly Ala Gly Gln Gln Pro
1 5 10 15
Gln Pro Gln Pro Gln Gln Pro Phe Leu Pro Pro Ala Ala Cys Phe Phe
20 25 30
Ala Thr Ala Ala Ala Ala Ala Ala Ala Ala Ala Ala Ala Ala Ala Gln
35 40 45
Ser Ala Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Ala Pro
50 55 60
Gln Leu Arg Pro Ala Ala Asp Gly Gln Pro Ser Gly Gly Gly His Lys
65 70 75 80
Ser Ala Pro Lys Gln Val Lys Arg Gln Arg Ser Ser Ala Pro Glu Leu
85 90 95
Met Arg Cys Lys Arg Arg Leu Asn Phe Ser Gly Phe Gly Tyr Ser Leu
100 105 110
Pro Gln Gln Gln Pro Ala Ala Val Ala Arg Arg Asn Glu Arg Glu Arg
115 120 125
Asn Arg Val Lys Leu Val Asn Leu Gly Phe Ala Thr Leu Arg Glu His
130 135 140
Val Pro Asn Gly Ala Ala Asn Lys Lys Met Ser Lys Val Glu Thr Leu
145 150 155 160
Arg Ser Ala Val Glu Tyr Ile Arg Ala Leu Gln Gln Leu Leu Asp Glu
165 170 175
His Asp Ala Val Ser Ala Ala Phe Gln Ala Gly Val Leu Ala Pro Thr
180 185 190
Ile Ala Pro Asn Tyr Ser Asn Asp Leu Asn Ser Met Ala Gly Ala Pro
195 200 205
Val Ser Ser Tyr Ser Ser Asp Glu Gly Ser Tyr Asp Pro Leu Ala Pro
210 215 220
Glu Glu Gln Glu Leu Leu Asp Phe Thr Asn Trp Phe
225 230 235
<210> 42
<211> 2209
<212> DNA
<213> Artificial Sequence
<220>
<223> Artificail Sequence
<400> 42
taatcccacc tccctctctg tgctgggact cacagaggga gacctcagga ggcagtctgt 60
ccatcacatg tccaaatgca gagcataccc tgggctgggc gcagtggcgc acaactgtaa 120
ttccagcact ttgggaggct gatgtggaag gatcacttga gcccagaagt tctagaccag 180
cctgggcaac atggcaagac cctatctcta caaaaaaagt taaaaaatca gccacgtgtg 240
gtgacacaca cctgtagtcc cagctattca ggaggctgag gtgaggggat cacttaaggc 300
tgggaggttg aggctgcagt gagtcgtggt tgcgccactg cactccagcc tgggcaacag 360
tgagaccctg tctcaaaaga caaaaaaaaa aaaaaaaaaa aaagaacata tcctggtgtg 420
gagtagggga cgctgctctg acagaggctc gggggcctga gctggctctg tgagctgggg 480
aggaggcaga cagccaggcc ttgtctgcaa gcagacctgg cagcattggg ctggccgccc 540
cccagggcct cctcttcatg cccagtgaat gactcacctt ggcacagaca caatgttcgg 600
ggtgggcaca gtgcctgctt cccgccgcac cccagccccc ctcaaatgcc ttccgagaag 660
cccattgagc agggggcttg cattgcaccc cagcctgaca gcctggcatc ttgggataaa 720
agcagcacag ccccctaggg gctgcccttg ctgtgtggcg ccaccggcgg tggagaacaa 780
ggctctattc agcctgtgcc caggaaaggg gatcagggga tgcccaggca tggacagtgg 840
gtggcagggg gggagaggag ggctgtctgc ttcccagaag tccaaggaca caaatgggtg 900
aggggactgg gcagggttct gaccctgtgg gaccagagtg gagggcgtag atggacctga 960
agtctccagg gacaacaggg cccaggtctc aggctcctag ttgggcccag tggctccagc 1020
gtttccaaac ccatccatcc ccagaggttc ttcccatctc tccaggctga tgtgtgggaa 1080
ctcgaggaaa taaatctcca gtgggagacg gaggggtggc cagggaaacg gggcgctgca 1140
ggaataaaga cgagccagca cagccagctc atgtgtaacg gctttgtgga gctgtcaagg 1200
cctggtctct gggagagagg cacagggagg ccagacaagg aaggggtgac ctggagggac 1260
agatccaggg gctaaagtcc tgataaggca agagagtgcc ggccccctct tgccctatca 1320
ggacctccac tgccacatag aggccatgat tgacccttag acaaagggct ggtgtccaat 1380
cccagccccc agccccagaa ctccagggaa tgaatgggca gagagcagga atgtgggaca 1440
tctgtgttca agggaaggac tccaggagtc tgctgggaat gaggcctagt aggaaatgag 1500
gtggcccttg agggtacaga acaggttcat tcttcgccaa attcccagca ccttgcaggc 1560
acttacagct gagtgagata atgcctgggt tatgaaatca aaaagttgga aagcaggtca 1620
gaggtcatct ggtacagccc ttccttccct tttttttttt tttttttgtg agacaaggtc 1680
tctctctgtt gcccaggctg gagtggcgca aacacagctc actgcagcct caacctactg 1740
ggctcaagca atcctccagc ctcagcctcc caaagtgctg ggattacaag catgagccac 1800
cccactcagc cctttccttc ctttttaatt gatgcataat aattgtaagt attcatcatg 1860
gtccaaccaa ccctttcttg acccaccttc ctagagagag ggtcctcttg cttcagcggt 1920
cagggcccca gacccatggt ctggctccag gtaccacctg cctcatgcag gagttggcgt 1980
gcccaggaag ctctgcctct gggcacagtg acctcagtgg ggtgagggga gctctcccca 2040
tagctgggct gcggcccaac cccaccccct caggctatgc cagggggtgt tgccaggggc 2100
acccgggcat cgccagtcta gcccactcct tcataaagcc ctcgcatccc aggagcgagc 2160
agagccagag caggttggag aggagacgca tcacctccgc tgctcgcgg 2209
<210> 43
<211> 683
<212> DNA
<213> Artificial Sequence
<220>
<223> Artificail Sequence
<400> 43
aacatatcct ggtgtggagt aggggacgct gctctgacag aggctcgggg gcctgagctg 60
gctctgtgag ctggggagga ggcagacagc caggccttgt ctgcaagcag acctggcagc 120
attgggctgg ccgcccccca gggcctcctc ttcatgccca gtgaatgact caccttggca 180
cagacacaat gttcggggtg ggcacagtgc ctgcttcccg ccgcacccca gcccccctca 240
aatgccttcc gagaagccca ttgagcaggg ggcttgcatt gcaccccagc ctgacagcct 300
ggcatcttgg gataaaagca gcacagcccc ctaggggctg cccttgctgt gtggcgccac 360
cggcggtgga gaacaaggct ctattcagcc tgtgcccagg aaaggggatc aggggatgcc 420
caggcatgga cagtgggtgg caggggggga gaggagggct gtctgcttcc cagaagtcca 480
aggacacaaa tgggtgaggg gagagctctc cccatagctg ggctgcggcc caaccccacc 540
ccctcaggct atgccagggg gtgttgccag gggcacccgg gcatcgccag tctagcccac 600
tccttcataa agccctcgca tcccaggagc gagcagagcc agagcaggtt ggagaggaga 660
cgcatcacct ccgctgctcg cgg 683
<210> 44
<211> 45
<212> PRT
<213> Artificial Sequence
<220>
<223> Artificail Sequence
<400> 44
Met Leu Gly Asp Gly Asp Ser Pro Gly Pro Gly Phe Thr Pro His Asp
1 5 10 15
Ser Ala Pro Tyr Gly Ala Leu Asp Met Ala Asp Phe Glu Phe Glu Gln
20 25 30
Met Phe Thr Asp Ala Leu Gly Ile Asp Glu Tyr Gly Gly
35 40 45
<210> 45
<211> 135
<212> DNA
<213> Artificial Sequence
<220>
<223> Artificail Sequence
<400> 45
atgttggggg acggggattc cccgggtccg ggatttaccc cccacgactc cgccccctac 60
ggcgctctgg atatggccga cttcgagttt gagcagatgt ttaccgatgc ccttggaatt 120
gacgagtacg gtggg 135
<210> 46
<211> 237
<212> DNA
<213> Artificial Sequence
<220>
<223> Artificail Sequence
<400> 46
cgatggagcg gagaatgggc ggaactgggc ggagttaggg gcgggatggg cggagttagg 60
ggcgggacta tggttgctga ctaattgaga tgcatgcttt gcatacttct gcctgctggg 120
gagcctgggg actttccaca cctggttgct gactaattga gatgcatgct ttgcatactt 180
ctgcctgctg gggagcctgg ggactttcca caccctaact gacacacatt ccacagc 237
Claims (20)
- 기능성 단편은 전사 인자의 발현을 촉진할 수 있는 적어도 하나의 기능성 단편을 포함하고,
상기 기능성 단편은 Ascl1, NeuroD1, Brn2, Ngn2, Gsx1, Tbr1, Dlx2, Ptf1a, Pax6 및/또는 Otx2 전사 인자의 발현을 촉진할 수 있는 것들로부터 선택되는 신경아교세포의 전환분화를 상승적으로 촉진할 수 있는 기능성 단편군. - 제 1 항에 있어서,
상기 Ascl1 은 강화된 Ascl1 이고, 그 아미노산 서열은 서열번호 41로 표시되는 것을 특징으로 하는 신경아교세포의 전환분화를 상승적으로 촉진할 수 있는 기능성 단편군. - 제 1 항에 있어서,
상기 기능성 단편은 전사 인자의 발현을 촉진하는 적어도 2개의 기능성 단편을 포함하고,
상기 기능성 단편은 NeuroD1, Brn2, Ascl1, Ngn2, Gsx1, Tbr1, Dlx2, Ptf1a, Pax6 및/또는 Otx2 전사 인자의 발현을 촉진할 수 있는 것들로부터 선택되며,
바람직하게는, 상기 기능성 단편은 적어도 Ascl1 및 Ngn2 전사 인자 중 어느 하나의 발현을 촉진할 수 있는 기능성 단편을 함유하는 것을 특징으로 하는 신경아교세포의 전환분화를 상승적으로 촉진할 수 있는 기능성 단편군. - 제 1 항에 있어서,
상기 기능성 단편은 적어도 NeuroD1 및 Brn2 전사 인자의 발현을 촉진하는 기능적 단편 또는 Gsx1 및 Tbr1 전사 인자의 발현을 촉진하는 기능성 단편, 또는 Dlx2 및 Ptf1a 전사 인자의 발현을 촉진하는 기능성 단편 또는 Pax6 및 Otx2 전사 인자의 발현을 촉진하는 기능적 단편을 포함하고, 바람직하게는 상기 기능성 단편은 Ascl1 또는 Ngn2 전사 인자의 발현을 촉진하는 기능성 단편을 포함하는 것을 특징으로 하는 신경아교세포의 전환분화를 상승적으로 촉진할 수 있는 기능성 단편군. - 제 1 항에 있어서,
상기 기능성 단편은 전사 인자를 암호화하는 폴리뉴클레오티드, 또는 폴리뉴클레오티드의 번역 후 기능성 단백질 및 펩티드, 또는 전사 인자의 발현을 촉진하는 소분자 약물, 거대분자 약물, 핵산 약물, 또는 폴리뉴클레오티드 또는 기능성 단백질, 펩티드, 소분자 약물 또는 거대분자 약물, 또는 전사 인자의 업스트림에 위치하고 전사 인자 발현의 상향 조절을 조절하는 핵산 약물로부터 선택되는 것을 특징으로 하는 신경아교세포의 전환분화를 상승적으로 촉진할 수 있는 기능성 단편군. - 제 4 항에 있어서,
상기 기능성 단편은 SEQ ID NO.: 1, 2, 5, 6, 9, 10, 13, 14, 17, 18, 21, 22, 25, 26, 29, 30, 33, 34, 37, 38 및/또는 41 와 85% 이상의 서열 상동성을 갖는 전사 인자 기능성 단백질 또는 SEQ ID NO.: 3, 4, 7, 8, 11, 12, 15, 16, 19, 20, 23, 24, 27, 28, 31, 32, 35, 36, 39 및/또는 40 과 75% 이상의 서열 상동성을 갖는 전사 인자를 코딩하는 폴리뉴클레오티드로부터 부터 선택되고,
바람직하게는 상기 기능성 단편은 SEQ ID NO.: 1, 2, 5, 6, 9, 10, 13, 14, 17, 18, 21, 22, 25, 26, 29, 30, 33, 34, 37, 38 및/또는 41 와 95% 이상의 서열 상동성을 갖는 전사 인자 기능성 단백질 또는 SEQ ID NO.: 3, 4, 7, 8, 11, 12, 15, 16, 19, 20, 23, 24, 27, 28, 31, 32, 35, 36, 39 및/또는 40 과 85% 이상의 서열 상동성을 갖는 전사 인자를 코딩하는 폴리뉴클레오티드로부터 부터 선택되며,
보다 바람직하게는 상기 기능성 단편은 SEQ ID NO.: 1, 2, 5, 6, 9, 10, 13, 14, 17, 18, 21, 22, 25, 26, 29, 30, 33, 34, 37, 38 및/또는 41 와 99% 이상의 서열 상동성을 갖는 전사 인자 기능성 단백질 또는 SEQ ID NO.: 3, 4, 7, 8, 11, 12, 15, 16, 19, 20, 23, 24, 27, 28, 31, 32, 35, 36, 39 및/또는 40 과 95% 이상의 서열 상동성을 갖는 전사 인자를 코딩하는 폴리뉴클레오티드로부터 부터 선택되는 것을 특징으로 하는 신경아교세포의 전환분화를 상승적으로 촉진할 수 있는 기능성 단편군. - 제 1 항에 있어서,
전사 인자의 발현을 촉진하는 상기 기능적 단편은 신경아교세포와 직접 접촉하거나 이를 전달계에 도입함으로써 신경아교세포에서 관련된 전사인자의 발현을 촉진할 수 있고, 기능적 신경세포 또는 신경유사세포의 특성을 나타내며,
바람직하게는, 신경아교세포는 성상세포, NG2 아교세포, 희소돌기아교세포, 미세아교세포 또는 손상된 상태의 아교세포, 및 아교세포로부터 유래된 종양 세포로부터 선택되고,
전달 시스템은 전사 인자의 발현을 촉진하는 기능적 단편을 포함하는 발현 벡터, 전사 인자의 발현을 촉진하는 기능적 단편으로 싸인 나노입자, 전사 인자의 발현을 촉진하는 기능적 단편으로 싸인 엑소좀, 전사 인자의 발현을 촉진하는 기능적 단편으로 포장된 바이러스 벡터 또는 세포 벡터, 및 전사 인자의 발현을 촉진하는 기능적 단편을 포함하는 표적화된 이펙터로부터 선택되며,
상기 전달 시스템은 신경아교세포 특이적 프로모터 또는 발현 조절 요소를 포함하는 것을 특징으로 하는 신경아교세포의 전환분화를 상승적으로 촉진할 수 있는 기능성 단편군. - 제 7 항에 있어서,
상기 전사 인자의 발현을 촉진하는 기능적 단편의 발현 시스템은 동일한 발현 벡터 상에 구성되거나 상이한 발현 벡터를 사용하여 개별적으로 발현되고,
(1) 전사 인자의 발현을 촉진하는 임의의 2개의 기능 단편이 있을 때, 2개의 전사 인자 발현의 몰 농도비는 4:1 내지 1:4이고; 바람직하게는, 두 전사 인자의 발현량의 몰 농도비는 2:1 내지 1:2; 보다 바람직하게는, 두 전사 인자 발현의 몰 농도 비율은 1:1이고; 또는
(2) 전사인자의 발현을 촉진하는 기능성 단편이 2개 이상 존재하고, 전사인자의 발현을 촉진하는 기능성 단편 중 하나가 Ascl1 또는 Ngn2 전사인자의 발현을 촉진하는 기능성 단편인 경우, Ascl1 또는 Ngn2 발현의 몰농도비가 20% 이상, 바람직하게는 Ascl1 또는 Ngn2 발현의 몰농도비가 33% 이상이고; 보다 바람직하게는 Ascl1 또는 Ngn2의 발현량의 몰농도비가 50% 이상인 것을 특징으로 하는 신경아교세포의 전환분화를 상승적으로 촉진할 수 있는 기능성 단편군. - 제 8 항에 있어서,
전사 인자의 발현을 촉진하는 기능성 단편은 하기로부터 선택되는 것을 특징으로 하는 신경아교세포의 전환분화를 상승적으로 촉진할 수 있는 기능성 단편군.
(1) NeuroD1 및 Brn2의 전사 인자의 발현을 촉진하는 기능적 단편의 조합;
(2) Gsx1 및 Tbr1 전사 인자의 발현을 촉진하는 기능적 단편의 조합;
(3) Dlx2 및 Ptf1a의 전사 인자의 발현을 촉진하는 기능적 단편의 조합;
(4) Pax6 및 Otx2 전사 인자의 발현을 촉진하는 기능적 단편의 조합;
(5) Ascl1 및 NeuroD1, Brn2, Ngn2, Gsx1, Tbr1, Dlx2, Ptf1a, Pax6 또는 Otx2에서 선택되는 다른 전사 인자 및 기타 전사 인자의 발현을 촉진하는 기능적 단편의 조합;
(6) NeuroD1, Brn2, Ascl1, Gsx1, Tbr1, Dlx2, Ptf1a, Pax6 또는 Otx2로부터 선택되는 Ngn2 및 임의의 다른 전사 인자 및 다른 전사 인자의 발현을 촉진하는 기능적 단편의 조합. - 제 8 항에 있어서,
전사 인자의 발현을 촉진하는 기능성 단편은 하기로부터 선택되는 것을 특징으로 하는 신경아교세포의 전환분화를 상승적으로 촉진할 수 있는 기능성 단편군.
(1) Ascl1, NeuroD1 및 Brn2의 전사 인자의 발현을 촉진하는 기능적 단편의 조합;
(2) Ascl1, Gsx1 및 Tbr1의 전사 인자의 발현을 촉진하는 기능적 단편의 조합;
(3) Ascl1, Dlx2 및 Ptf1a의 전사 인자의 발현을 촉진하는 기능적 단편의 조합;
(4) Ascl1, Pax6 및 Otx2의 전사 인자의 발현을 촉진하는 기능적 단편의 조합;
(5) Ngn2, NeuroD1 및 Brn2의 전사 인자의 발현을 촉진하는 기능적 단편의 조합;
(6) Ngn2, Gsx1 및 Tbr1의 전사 인자의 발현을 촉진하는 기능적 단편의 조합;
(7) Ngn2, Dlx2 및 Ptf1a의 전사 인자의 발현을 촉진하는 기능적 단편의 조합;
(8) Ngn2, Pax6 및 Otx2의 전사 인자의 발현을 촉진하는 기능적 단편의 조합;
그 중 Ascl1이나 Ngn2를 제외한 나머지 두 전사인자의 발현 몰농도비는 4:1 내지 1:4이고; 바람직하게는, 나머지 2개의 전사 인자의 발현량의 몰 농도비는 2:1 내지 1:2; 보다 바람직하게는 나머지 2개의 전사인자 발현의 몰농도비는 약 1:1 이다. - 제 1 항에 있어서,
상기 전환분화는 신경아교세포의 기능성 뉴런으로의 전환분화 또는 재프로그래밍을 의미하는 것을 특징으로 하는 신경아교세포의 전환분화를 상승적으로 촉진할 수 있는 기능성 단편군. - 제 1 항에 있어서,
상기 기능성 단편의 조합은 하기 그룹으로부터 선택되는 것을 특징으로 하는 신경아교세포의 전환분화를 상승적으로 촉진할 수 있는 기능성 단편군.
(Z1) NeuroD1+Brn2;
(Z2) Ascl1+Ngn2;
(Z3) Ngn2+NeuroD1;
(Z4) Gsx1+Tbr1;
(Z5) Dlx2+Ptf1a;
(Z6) Pax6+Otx2;
(Zn) 상기 (Z1) 내지 (Z6)의 조합. - 제 1 항에 있어서,
기능성 단편의 조합은 하기 그룹으로부터 선택되는 것을 특징으로 하는 신경아교세포의 전환분화를 상승적으로 촉진할 수 있는 기능성 단편군.
NeuroD1+Brn2;
Gsx1+Tbr1;
Dlx2+Ptf1a; Pax6+Otx2; 또는 이들의 조합. - 하기 단계를 포함하는 신경아교세포의 기능성 뉴런 또는 뉴런 유사 세포로의 전환분화 및 재프로그래밍을 촉진하는 방법:
신경아교세포와 신경아교세포의 전환분화를 상승적으로 촉진할 수 있는 제1항 내지 제13항에 기재된 임의의 기능적 단편을 접촉시켜, 신경교세포의 기능적 뉴런 또는 뉴런-유사 세포로의 전환분화 및 재프로그래밍을 가능하게 하는 단계. - 제14항에 기재된 방법에 의해 제조된 인공 재프로그래밍된 뉴런 또는 뉴런 유사체.
- 신경계 질환에 대한 약물의 제조에서 제1항 내지 제13항 중 어느 한 항에 기재된 바와 같이 신경아교세포의 전환분화를 상승적으로 촉진할 수 있는 기능성 단편의 적용,
상기 신경계 질환은 신경계 질환, 손상 또는 신경아교세포로부터 유래된 신경아교종인 것을 특징으로 한다. - 하기를 포함하는 약제학적 조성물:
(A) 전사 인자의 발현을 촉진하는 기능적 단편, 또는 그 조합으로 신경아교세포 전환분화 및 재프로그래밍을 처리하여 얻은 기능적 뉴런 또는 신경유사 요소의 조합;
상기 조합은 Ascl1 또는 향상된 Ascl1; 또는 Ngn2; 또는 하기 그룹에서 선택된 조합
(Z1) NeuroD1+Brn2;
(Z2) Ascl1+Ngn2;
(Z3) Ngn2+NeuroD1;
(Z4) Gsx1+Tbr1;
(Z5) Dlx2+Ptf1a;
(Z6) Pax6+Otx2; 그리고
(Zn) 상기 (Z1) 내지 (Z6)의 조합,
(B) 약제학적으로 허용되는 부형제. - 제 17 항에 있어서,
상기 조합은 강화된 Ascl1과 NeuroD1, Brn2, Ngn2, Gsx1, Tbr1, Dlx2, Ptf1a, Pax6, Otx2 그룹으로부터 선택되는 적어도 하나의 조합인 것을 특징으로 하는 약제학적 조성물. - 제 17 항에 있어서,
상기 조합은 Ascl1과 NeuroD1, Brn2, Ngn2, Gsx1, Tbr1, Dlx2, Ptf1a, Pax6, Otx2 그룹으로부터 선택되는 적어도 하나의 조합인 것을 특징으로 하는 약제학적 조성물. - 제 17 항에 있어서,
상기 조합은 Ngn2와 NeuroD1, Brn2, Ngn2, Gsx1, Tbr1, Dlx2, Ptf1a, Pax6, Otx2 그룹으로부터 선택된 적어도 하나의 조합인 것을 특징으로 하는 약제학적 조성물.
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