KR20230152945A - Cdon-Ig2 도메인 단백질을 포함하는 혈관 석회화 치료용 조성물 - Google Patents
Cdon-Ig2 도메인 단백질을 포함하는 혈관 석회화 치료용 조성물 Download PDFInfo
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Abstract
본 발명은 Cdon-Ig2 도메인 또는 이로부터 유래되는 펩타이드의 혈관 석회화 및 이와 관련된 혈관 질환의 예방, 개선 또는 치료용 조성물, 상기 펩타이드의 발현량 확인을 통해 혈관 석회화와 관련된 질환의 진단에 대한 정보를 제공하는 방법에 대한 것이다.
Description
본 발명은 Cdon-Ig2 도메인 또는 이로부터 유래되는 펩타이드의 혈관 석회화 및 이와 관련된 혈관 질환의 예방, 개선 또는 치료 용도와, 상기 펩타이드의 발현을 통해 혈관 석회화와 관련된 정보를 제공하는 방법에 대한 것이다.
혈관 석회화(Vascular calcification)는 혈관에 칼슘이 쌓여 딱딱하게 굳어지는 질환으로, 동맥 경화증 환자에서 많이 관찰되며 대동맥 및 동맥 탄성을 감소시킬 수 있다. 혈관의 석회화는 발생되는 부위에 따라 내막 석회화(AIC (arterial intimal calcification))와 중막 석회화(AMC (arterial medial calcification))로 나누어질 수 있으며, 특히 혈관의 내막 석회화는 죽상동맥경화증(atherosclerosis)과 연관되어 발생하고, 중막 석회화는 제2형 당뇨병 환자 및 말기 신질환 환자에서 흔히 관찰되며 이러한 유형의 석회화를 묀케베르그 내측 경화증(MMS)이라고도 부른다. 혈관 석회화는 혈관 경화를 유발하고, 수축기 고혈압 및 혈압 변동을 유발하여 결국 심장 비대, 심근 허혈, 말초 동맥 허혈 및 울혈성 심부전으로 이어질 수 있다.
Cdon(CAM-related/downregulated by oncogenes)은 세포 부착 분자의 면역글로불린/피브로넥틴 유형 III 슈퍼패밀리의 구성원으로, Cdon이 Shh, Wnt 및 N-cadherin/세포 부착 신호의 조절을 통해 전뇌 및 골격근의 발달에 중요한 역할을 하는 것을 이전 연구를 통해 확인하였다. Cdon은 Shh 신호전달 활성화 외에도, Lrp6 공동수용체와의 상호작용을 통해 Wnt 신호전달을 억제하여 초기 전뇌 발달에서 복부 신경 세포 발달을 촉진한다. 또한, Wnt 신호에 대한 Cdon의 억제 활성은 심장 리모델링 및 섬유증의 예방에서도 입증되었다. 즉, 여러 가지 연구를 통하여, Cdon이 Wnt 신호 전달을 억제하는 활성을 가지거나, Cdon이 과발현된 경우 Wnt 신호가 억제되어 이후의 골형성, 신경세포의 발달 또는 심장 리모델링 등의 일련의 과정에 영향을 줄 수 있다는 점을 확인한 바 있다.
만성신장질환(CKD) 환자는 심각한 동맥 석회화를 보이며 심혈관 질환 발병률이 높으며, 무기질 및 골 질환 환자의 혈액 내 높은 인산염 농도는 Wnt/β-Catenin 신호전달을 활성화하여 혈관 석회화를 유도할 수 있다. 클로토(Klotho) 돌연변이(kl/kl) 마우스는 혈관 내측 석회화를 비롯한 심각한 조직 칼슘 침착을 보여준다. 클로토는 여러 Wnt 리간드에 결합하여 Wnt 신호전달 활성화를 억제하는 것으로 알려져 있으며, 따라서 kl/kl 마우스에서 Wnt 신호 전달이 활성화된다. 클로토는 주로 신장에서 생성되며 분비된 형태는 혈액으로 방출되는데, CKD 환자는 클로토 생성이 감소되어 있는 것으로 나타난다. 즉, 클로토 생성이 감소된 경우 Wnt 신호전달 경로가 활성화될 수 있는데, 이 경우 Wnt 신호전달 경로의 조절을 통하여 혈관 석회화를 치료할 수 있는지에 대한 연구가 필요한 실정이다.
따라서, 본 발명자들은 Wnt 신호 전달 경로에 관여하는 다양한 인자 중, 혈관 석회화를 치료할 수 있는 물질에 대한 연구를 진행한 끝에 본 발명을 완성하게 되었다.
본 발명자들은 Wnt/β-Catenin 신호 전달 경로에 관여하는 인자 중, Cdon-Ig2 도메인이 혈관 석회화와 관련되어 있으며, 이를 치료할 수 있다는 것을 발견하고, 본 발명을 완성하였다.
따라서 본 발명의 목적은 Cdon-Ig2 도메인 또는 이로부터 유래되는 펩타이드를 혈관 석회화 또는 혈관 질환의 예방, 개선 또는 치료용 조성물로 제공하는 것이다.
본 발명의 다른 목적은 Cdon-Ig2 도메인 또는 이로부터 유래된 펩타이드를 암호화하는 폴리뉴클레오티드를 포함하는 벡터, 그리고 상기 벡터가 형질 감염된 세포를 혈관 석회화 또는 혈관 질환의 예방, 개선 또는 치료용 조성물로 제공하는 것이다.
본 발명의 또 다른 목적은 1)실험군으로서 피검체 유래 시료에서 Cdon-Ig2 도메인 또는 이로부터 유래한 펩타이드의 발현량을 측정하는 단계;
2)상기 Cdon-Ig2 도메인 또는 이로부터 유래한 펩타이드의 발현량과 대조군으로서 정상 개체 유래 시료의 Cdon-Ig2 도메인 또는 이로부터 유래한 펩타이드의 발현량을 비교하는 단계; 및
3) Cdon-Ig2 도메인 또는 이로부터 유래한 펩타이드의 발현량이 대조군에 비해 감소하는 경우 혈관 석회화 또는 이와 관련된 혈관 질환에 걸릴 위험이 높은 것으로 판정하는 단계를 포함하는, 혈관 석회화 또는 혈관 질환에 대한 정보를 제공하기 위한 방법을 제공하는 것이다.
상기와 같은 목적을 달성하기 위하여, 본 발명은 Cdon-Ig2 도메인 또는 이로부터 유래되는 펩타이드를 혈관 석회화 또는 혈관 질환의 예방, 개선 또는 치료용 조성물로 제공한다.
본 발명의 다른 목적을 달성하기 위하여 본 발명은 Cdon-Ig2 도메인 또는 이로부터 유래한 펩타이드를 암호화하는 폴리뉴클레오티드를 포함하는 벡터, 그리고 상기 벡터가 형질 감염된 세포를 포함하는 혈관 석회화 또는 혈관 질환의 예방, 개선 또는 치료용 조성물로 제공한다.
본 발명의 또 다른 목적을 달성하기 위하여 본 발명은 1)실험군으로서 피검체 유래 시료에서 Cdon-Ig2도메인 또는 이로부터 유래한 펩타이드의 발현량을 측정하는 단계;
2)상기 Cdon-Ig2 도메인 또는 이로부터 유래한 펩타이드의 발현량과 대조군으로서 정상 개체 유래 시료의 Cdon-Ig2 도메인 또는 이로부터 유래한 펩타이드의 발현량을 비교하는 단계; 및
3) Cdon-Ig2 도메인 또는 이로부터 유래한 펩타이드의 발현량이 대조군에 비해 감소하는 경우 혈관 석회화 또는 이와 관련된 혈관 질환에 걸릴 위험이 높은 것으로 판정하는 단계를 포함하는, 혈관 석회화 또는 혈관 질환에 대한 정보를 제공하기 위한 방법을 제공한다.
이하, 본 발명을 상세하게 설명한다.
본 발명은 혈관 석회화 또는 이와 관련된 혈관 질환에 대한 예방, 개선 또는 치료용 약학 조성물로서 Cdon-Ig2 도메인 또는 이로부터 유래되는 펩타이드에 대한 것이다.
세포 표면 단백질인 Cdon(Cdo이라고도 함)은 근육 분화에 관여하는 면역 글로불린/피브로넥틴 III 형 반복 패밀리의 세포 표면 수용체이다. Cdon은 골격근아세포 사이의 접촉 부위에서 N-cadherin과 복합체를 형성하며, 이러한 상호 작용은 Cdon에 의한 근육세포 분화 촉진 기능에 중요한 영향을 주는 것으로 알려져 있다. Cdon이 발현되는 다양한 운동 신경 또는 신경 근육 접합부에서의 기전에 대해서는 알려진 바가 없다. 또한, 본 발명자들은 선행 연구를 통해 Cdon이 Lrp6와 결합하여 Wnt 신호전달 경로를 저해한다는 사실을 확인하였다. 본 발명에서는 Cdon의 Ig2 도메인이 혈관 석회화를 저해하는 효과를 확인하였으며, 이를 통해 혈관 석회화와 관련된 질환에 대한 예방, 개선 또는 치료 용도로서 활용할 수 있음을 확인하였다.
본 발명의 상기 Cdon-Ig2 도메인은 구체적으로, 서열번호 1 또는 서열번호 2의 아미노산 서열로 이루어진 포유류의 Cdo 또는 Cdon으로부터 유래된 펩타이드 또는 이의 절편을 포함하는 것으로, 보다 구체적으로는 서열번호 3 내지 서열번호 4의 아미노산 서열로 이루어진 펩타이드를 포함하는 것일 수 있다. 또한 상기 Cdon-Ig2 도메인은 인공적으로 합성된 서열을 포함하는 펩타이드일 수 있으며, 구체적으로 서열번호 5 내지 서열번호 11의 아미노산 서열을 포함하는 펩타이드일 수 있고, 보다 구체적으로 서열번호 7 내지 서열번호 10의 아미노산 서열을 포함하는 펩타이드일 수 있다.
본 발명의 다른 양태로서 본 발명은 상기 Cdon-Ig2 도메인 또는 이로부터 유래한 펩타이드를 암호화하는 폴리뉴클레오티드를 포함하는 벡터, 그리고 상기 벡터가 형질 감염된 세포를 이용한 혈관 석회화 또는 이와 관련된 혈관 질환의 예방, 개선 또는 치료용 조성물에 대한 것이다.
상기 Cdon-Ig2 도메인 또는 이로부터 유래한 펩타이드의 폴리뉴클레오티드를 포함하는 벡터는 그 종류에 제한되는 것은 아니며, 생체 내 또는 생체 외에서 Cdon-Ig2 도메인 또는 이로부터 유래한 펩타이드를 발현할 수 있는 것이면 제한 없이 사용할 수 있다. 구체적으로, 인체 또는 동물세포에서 발현되는 선형 DNA, 플라스미드 벡터, 재조합 바이러스성 벡터를 포함하는 벡터일 수 있고, 상기 재조합 바이러스성 벡터는 재조합 레트로바이러스(retrovirus) 벡터, 재조합 아데노바이러스(adenovirus) 벡터, 재조합 아데노 부속 바이러스(adeno-associated virus, AAV)벡터, 재조합 헤르페스 심플렉스 바이러스(herpes simplex virus) 벡터 또는 재조합 렌티바이러스(lentivirus)벡터를 포함하는 것이 바람직하나 이에 한정되지 않는다.
또한 상기 Cdon-Ig2 도메인 또는 이로부터 유래한 펩타이드를 암호화하는 폴리뉴클레오티드를 포함하는 벡터가 형질 감염된 세포는 혈관 세포로서, 혈관 근육세포, 혈관 평활근 세포(vascular smooth muscle cells), 혈관 내피세포(vascular endothelial cell), 혈관모세포(angioblast) 또는 혈관 줄기세포 중 선택할 수 있다.
본 발명에서 용어 '혈관 석회화'는 체내 칼슘이 정상적으로 이용되지 않고, 노폐물과 함께 혈관 벽이나 장기 세포에 침착하여 생기는 현상을 말한다. 상기 혈관 석회화는 발병 부위에 따라, 내막 석회화(AIC), 중막 석회화(AMC)로 구분될 수 있으며, 본 발명의 혈관 석회화는 이를 모두 포함한다. 또한 이러한 혈관 석회화로 인하여 유발될 수 있는 관련 증상 또는 혈관 질환에는 심근 경색, 혈관(동맥)경화, 고혈압, 허혈성 심장 질환, 관류 장애, 심장 비대증, 좌심실 비대증, 심근 허혈, 말초 동맥 허혈 및 심부전이 포함될 수 있으며, 이외에도 혈관 석회화로 인하여 발생되는 혈관 질환은 제한 없이 포함될 수 있다. 본 발명의 Cdon-Ig2 도메인 또는 이로부터 유래된 펩타이드는 혈관 석회화에 대한 개선을 통하여 상기 질환들에 대한 치료 효과를 나타낼 수 있다.
즉, 본 발명에서 Cdon-Ig2 도메인의 상기 혈관 질환에 대한 예방, 치료 또는 개선 효과는 혈관 석회화의 감소에 의한 것이다. 본 발명의 일 실시예에서는 상기 Cdon에 포함되는 Cdon-Ig2 도메인이 혈관 석회화와 관련된 조절 인자의 발현에 영향을 미침을 확인하였다. 본 발명의 일 실시예에서 확인한 바, 마우스의 혈관 평활근 세포(A7r5 세포)를 이용하여, 인위적으로 혈관 석회화를 유도한 경우, 골세포 분화 마커인 Runx2와 ALPL의 발현량이 상대적으로 증가되었으나, Cdon 발현량은 급격히 감소되었다. 또한, Cdon의 발현을 결손시킨 경우에도, Runx2, ALPL의 발현량이 상대적으로 증가되고 혈관 석회화가 증가되는 것을 확인하였다. 이로부터, Cdon이 혈관 석회화와 밀접한 관련이 있음을 확인하였다.
본 명세서에서 용어 "예방"은 본 발명에 따른 상기 약학적 조성물의 투여에 의해 혈관 석회화를 억제시키거나 발병을 지연시킬 수 있는 모든 행위를 의미한다.
본 명세서에서 용어 "치료"는 본 발명에 따른 상기 약학적 조성물의 투여에 의해 증세가 호전되거나 이롭게 되는 모든 행위를 말한다.
본 발명의 상기 약학적 조성물은 통상의 방법에 따라 산제, 과립제, 정제, 캡슐제, 현탁액, 에멀젼, 시럽, 에어로졸 등의 경구형 제형, 외용제, 좌제 및 멸균 주사용액의 형태로 제형화하여 사용될 수 있으며, 상기 제형화에 필요한 담체 혹은 부형제 등을 추가로 포함할 수 있다. 상기 유효 성분에 추가로 포함될 수 있는 약학적으로 허용 가능한 담체, 부형제 및 희석제로는 락토즈, 덱스트로즈, 수크로스, 솔비톨, 만니톨, 자일리톨, 에리스리톨, 말티톨, 전분, 아카시아 고무, 알지네이트, 젤라틴, 칼슘 포스페이트, 칼슘 실리케이트, 셀룰로즈, 메틸 셀룰로즈, 미정질 셀룰로스, 폴리비닐 피롤리돈, 물, 메틸히드록시벤조에이트, 프로필히드록시벤조에이트, 마그네슘 스테아레이트 및 광물유 등이 포함된다. 제제화할 경우에는 보통 사용하는 충진제, 증량제, 결합제, 습윤제, 붕해제, 계면활성제 등의 희석제 또는 부형제를 사용하여 조제된다.
예를 들어, 경구 투여를 위한 고형 제제에는 정제, 환제, 산제, 과립제, 캡슐제 등이 포함되며, 이러한 고형제제는 상기 추출물 또는 화합물에 적어도 하나 이상의 부형제 적어도 면, 전분, 칼슘카보네이트 (calcium carbonate), 수크로스 (sucrose) 또는 락토오스 (lactose), 젤라틴 등을 섞어 조제된다. 또한 단순한 부형제 이외에 마그네슘 스티레이트 탈크 같은 윤활제들도 사용된다. 경구 투여를 위한 액상 제제로는 현탁제, 내용액제, 유제, 시럽제 등이 해당되는데 흔히 사용되는 단순희석제인 물, 리퀴드 파라핀 이외에 여러 가지 부형제, 예를 들면 습윤제, 감미제, 방향제, 보존제 등이 포함될 수 있다.
비경구 투여를 위한 제제에는 멸균된 수용액, 비수성용제, 현탁제, 유제, 동결건조제제, 좌제가 포함된다. 비수성용제, 현탁제로는 프로필렌글리콜 (propylene glycol), 폴리에틸렌 글리콜, 올리브 오일과 같은 식물성 기름, 에틸올레이트와 같은 주사 가능한 에스테르 등이 사용될 수 있다. 좌제의 기제로는 위텝솔 (witepsol), 마크로골, 트윈 (tween) 61, 카카오지, 라우린지, 글리세로젤라틴 등이 사용될 수 있다.
본 발명의 약학적 조성물은 목적하는 방법에 따라 경구 또는 비경구 투여(정맥주사, 피하, 복강 내 또는 국소에 적용)될 수 있으며, 투여량은 환자의 상태 및 체중, 질병의 정도 및 약물 형태, 투여 경로 및 시간에 따라 다르며, 당업자에 의해 적절한 형태로 선택될 수 있다.
본 발명의 상기 약학적 조성물은, 약학적으로 유효한 양으로 투여한다. 본 발명에서 "약학적으로 유효한 양"이란 의학적 치료에 적용 가능한 합리적인 양으로, 질병을 치료하기에 충분한 양을 의미하며, 그 기준은 환자의 질환, 중증도, 약물 활성, 약물에 대한 민감도, 투여 시간, 투여 경로 및 배출 비율, 치료 기간, 병용되는 성분 및 기타 사항에 따라 결정될 수 있다. 본 발명의 상기 약학적 조성물은, 개별 치료제 혹은 다른 치료제와 병용하여 투여될 수 있고, 종래의 치료제와는 순차적 또는 동시에 투여될 수 있다. 상기 요소들을 모두 고려하여 부작용을 최소화할 수 있는 수준으로 투여량을 결정할 수 있고, 이는 당업자에 의해 용이한 수준으로 결정될 수 있다. 구체적으로 상기 약학적 조성물의 투여량은 환자의 연령, 체중, 중증도, 성별 등에 따라 달라질 수 있으며, 일반적으로 체중 1kg 당 0.001 내지 150mg, 보다 바람직하게는 0.01 내지 100mg의 양을 매일 또는 격일, 1일 1 내지 3회 투여할 수 있다. 다만, 이는 예시적인 것으로, 상기 투여량은 필요에 달리 설정할 수 있다.
또한 본 발명의 일 양태로서 본 발명은 Cdon-Ig2 도메인 또는 이로부터 유래되는 펩타이드를 포함하는, 혈관 석회화 또는 이와 연관된 혈관 질환의 예방 또는 개선용 건강식품 조성물에 대한 것이다. 상기 "건강기능식품"은 건강기능식품에 관한 법률 제6727호에 따른 인체에 유용한 기능성을 가진 원료나 성분을 사용하여 제조 및 가공한 식품을 의미하며, "기능성"이라 함은 인체의 구조 및 기능에 대하여 영양소를 조절하거나 생리학적 작용 등과 같은 보건 용도에 유용한 효과를 얻을 목적으로 섭취하는 것을 의미한다.
본 발명의 상기 식품 또는 건강기능식품은, 혈관 석회화 및 관련 질환의 예방 및 개선을 위한 목적으로 산제, 과립제, 정제, 캡슐제, 환제, 현탁액, 에멀젼, 시럽 등 약학적 투여 형태 또는 티백, 침출자, 음료, 캔디, 젤리, 껌 등의 건강 기능식품으로 제조 및 가공이 가능하다.
본 발명의 상기 식품 또는 건강기능식품 조성물은, 식품 첨가물로 사용될 수 있으며, 단독으로 혹은 다른 성분과 조합하여 제품화될 수 있다. 또한, 영양제, 비타민, 전해질, 풍미제, 착색제 및 증진제, 펙트산 및 이의 염, 알긴산 및 이의 염, 유기산, 보호성 콜로이드 증점제, pH 조절제, 안정화제, 방부제, 글리세린, 알콜, 탄산 음료에 사용되는 탄산화제 등이 포함될 수 있다. 상기 성분은 단독 혹은 조합하여 사용될 수 있으며, 적절한 함량으로 조합되어 사용할 수 있다.
본 발명의 다른 양태로서, 본 발명은 혈관 석회화 또는 이와 연관된 혈관 질환에 대한 정보를 제공하는 방법으로서,
1)실험군으로서 피검체 유래 시료에서 Cdon-Ig2 도메인 또는 이로부터 유래한 펩타이드의 발현량을 측정하는 단계;
2)상기 Cdon-Ig2 도메인 또는 이로부터 유래한 펩타이드의 발현량과 대조군으로서 정상 개체 유래 시료의 Cdon-Ig2 도메인 또는 이로부터 유래한 펩타이드의 발현량을 비교하는 단계; 및
3) Cdon-Ig2 도메인 또는 이로부터 유래한 펩타이드의 발현량이 대조군에 비해 감소하는 경우 혈관 석회화 또는 이와 관련된 혈관 질환에 걸릴 위험이 높은 것으로 판정하는 단계를 포함하는, 혈관 석회화 또는 혈관 질환에 대한 정보를 제공하기 위한 방법을 제공한다.
본 발명의 일 실시예에서, Cdon의 발현이 억제된 경우, 혈관 석회화가 유도될 수 있으며, 반대로 Cdon의 발현을 유도한 경우, 혈관 석회화가 감소되는 것을 확인하였다. 따라서 Cdon의 발현 여부를 확인하여, 혈관 석회화 또는 이와 연관된 질환에 대한 발병 여부를 진단할 수 있다. 상기 진단의 정보를 제공하기 위한 검출 방법에 있어서, 단계 1)의 Cdon-Ig2 도메인 또는 이로부터 유래한 펩타이드의 발현량은 웨스턴 블랏(Western blotting), 실시간 중합효소 연쇄반응(qRT-PCR), 효소-면역화학 검출법(Enzyme-linked immunosorbent assay, ELISA), 면역 조직 화학 염색법(immunohistochemical staining), 면역침강(immunoprecipitation) 및 면역형광법(immunofluorescence)으로 구성된 군으로부터 선택되는 어느 하나의 방법으로 검출하는 것이 바람직하나, 이에 한정되지 않는다.
따라서, 본 발명의 Cdon-Ig2 도메인 또는 이로부터 유래한 펩타이드는 석회화와 관련된 인자의 발현을 감소시켜, 혈관 세포에서 석회화 및 이와 관련된 혈관 질환을 완화하며, 이러한 상기 석회화 관련 인자에 대한 발현 여부를 통해 혈관 석회화 또는 혈관 질환에 대한 발병 여부를 진단할 수 있으므로, Cdon-Ig2 도메인 또는 이로부터 유래한 펩타이드는 혈관 석회화 및 이와 연관된 혈관 질환의 치료 및 진단에 활용될 수 있다.
본 발명은 Cdon-Ig2 도메인 또는 이로부터 유래되는 펩타이드의 혈관 석회화 및 이와 관련된 혈관 질환의 예방, 개선 또는 치료 용도와 관련된 것으로, Cdon-Ig2 도메인은 혈관 석회화를 완화할 수 있는 효과를 가지므로, 이를 이용하여 혈관 석회화 및 관련 질환에 대한 약학적 또는 건강기능식품 조성물로 사용될 수 있으며, 혈관 석회화 및 혈관 질환의 진단과 관련된 정보를 제공하는 데 사용할 수 있다.
도 1은 랫트 Cdon-Ig2 도메인을 이용하여 인공적으로 합성한 Cdon-Ig2 펩타이드 서열 및 이의 3차원적 구조를 도식화한 것이다.
도 2는 혈관 석회화를 유도하기 위하여 혈관 평활근 세포(A7r5 세포)를 혈관 석회화 배양액에서 배양한 후, 석회화가 유도된 것을 확인한 도이다.
도 3은 석회화가 유도된 혈관 평활근 세포에서 골 형성 마커인 Runx2 및 ALPL의 발현이 증가된 것을 실시간 중합효소 연쇄반응을 수행하여 확인한 도이다. (데이터는 스튜던트 t-검정으로 분석된 ±SEM으로, **p<0.01, ***p<0.005)
도 4는 석회화가 유도된 혈관 평활근 세포(vascular smooth muscle cells, VSMC)에서 골 형성 마커의 증가 대비 Cdon의 발현량이 감소된 것을 확인한 도이다.(데이터는 스튜던트 t-검정으로 분석된 평균 ± SEM, *p<0.05)
도 5a는 비타민 D3(VD3)를 주입하여 석회화가 유도된 대동맥에서 Cdon과 αSMA의 면역염색 이미지이다. (Bar: 100μm(첫 번째) 및 50μm(두 번째)) 도 5b는 측정된 면역 염색 이미지의 형광 강도를 기반으로, αSMA의 강도로 정규화하여 정량화된 Cdon의 발현 수준을 나타낸 것이며, (n=4, 데이터는 스튜던트 t-검정으로 분석된 ±SEM으로, *p<0.05). 도 5c는 Cdon의 상대적 mRNA 발현 수준을 나타낸 것이다. (데이터는 스튜던트 t-검정으로 분석된 ±SEM으로, **p<0.01)
도 6은 Cdon을 결손시킨 혈관 평활근 세포를 석회화 배지에서 배양하여 석회화를 유도한 것을 알리자린 레드 염색으로 확인한 것이다. (Scale bar: 100μm)
도 7은 Cdon을 결손시킨 후 석회화가 유도된 혈관 평활근 세포(A7r5 세포)에서 골 형성 마커인 Runx2 및 ALPL의 상대적 mRNA 수준을 측정한 결과이다. (데이터는 스튜던트 t-검정으로 분석된 ±SEM으로, **p<0.01, ***p<0.005)
도 8은 shCdon을 포함한 렌티바이러스에 감염되어 Cdon이 결손된 혈관 평활근 세포(A7r5 세포)의 면역블롯 분석 결과이다.
도 9는 Cdon을 결손시킨 마우스(cKO)의 혈관 평활근에 VD3를 주입한 후, 석회화가 일어나는 면적과 골 형성 마커인 Runx2의 발현량을 각각 Von Kossa 염색과 면역형광 염색으로 확인한 것이다. (Scale bar: 100μm (위), 40μm (아래))
도 10은 Cdon을 결손시킨 마우스 모델과 정상군에 혈관 경화를 유도한 후, 맥파 전달속도(PWV)의 변화를 비교한 결과이다. (데이터는 스튜던트 t-검정으로 분석된 ±SEM으로, *p<0.05, ***p<0.005)
도 11은 Cdon (WT) 또는Ig2도메인이 제거된 Cdon(ΔIg2)을 발현시킨 혈관 평활근 세포에서 면역 블롯을 수행하여 b-Catenin과 Runx2의 발현을 분석한 결과이다.
도 12는 석회화 배지에 의해 석회화가 유도된 Cdon 또는 ΔIg2 발현 VSMC에서, Wnt 신호전달의 주요인자인 Axin2의 상대적 발현량을 나타낸 것이다. (데이터는 일원 분산 분석에 의해 분석된 ±SEM, n.s.=유의하지 않음, *p<0.05, **p<0.01)
도 13은 석회화 배지에 의해 석회화가 유도된 Cdon 또는 ΔIg2 발현 VSMC에서의 알리자린 레드 염색 이미지와 이를 정량화 한 그래프이다. (Scale bar: 100μm)
도 14는 Cdon-Fc 단백질(Cdon의 엑토도메인 전체가 Fc에 융합된 단백질)과 Ig2-Fc 단백질(Cdon-Ig2 도메인이 Fc에 융합된 단백질)을 나타낸 도이다.
도 15는 상기 도 14의 정제된 단백질이 함유된 석회화 배지에서 배양된 혈관 평활근 세포에서 b-Catenin과 Runx2의 발현을 면역블롯으로 분석한 결과이다.
도 16은 Cdon-Fc 또는 Ig2-Fc가 처리된 석회화 배지에서 배양된 혈관 평활근 세포의 알리자린 레드 염색 이미지 및 이를 정량화한 그래프를 나타낸 것이다. (데이터는 일원 분산 분석 테스트에 의해 분석된 ±SEM, ***p<0.005)
도 17은 Cdon-Fc 및 Ig2-Fc가 처리된 석회화 배지에서 배양된 혈관 평활근 세포에서 Wnt 신호전달 마커인 Axin2와 골 형성 마커인 Runx2, ALPL의 mRNA 발현량 차이를 나타낸 도이다. (데이터는 스튜던트 t-검정으로 분석된 ±SEM으로, *p<0.05, ***p<0.005)
도 2는 혈관 석회화를 유도하기 위하여 혈관 평활근 세포(A7r5 세포)를 혈관 석회화 배양액에서 배양한 후, 석회화가 유도된 것을 확인한 도이다.
도 3은 석회화가 유도된 혈관 평활근 세포에서 골 형성 마커인 Runx2 및 ALPL의 발현이 증가된 것을 실시간 중합효소 연쇄반응을 수행하여 확인한 도이다. (데이터는 스튜던트 t-검정으로 분석된 ±SEM으로, **p<0.01, ***p<0.005)
도 4는 석회화가 유도된 혈관 평활근 세포(vascular smooth muscle cells, VSMC)에서 골 형성 마커의 증가 대비 Cdon의 발현량이 감소된 것을 확인한 도이다.(데이터는 스튜던트 t-검정으로 분석된 평균 ± SEM, *p<0.05)
도 5a는 비타민 D3(VD3)를 주입하여 석회화가 유도된 대동맥에서 Cdon과 αSMA의 면역염색 이미지이다. (Bar: 100μm(첫 번째) 및 50μm(두 번째)) 도 5b는 측정된 면역 염색 이미지의 형광 강도를 기반으로, αSMA의 강도로 정규화하여 정량화된 Cdon의 발현 수준을 나타낸 것이며, (n=4, 데이터는 스튜던트 t-검정으로 분석된 ±SEM으로, *p<0.05). 도 5c는 Cdon의 상대적 mRNA 발현 수준을 나타낸 것이다. (데이터는 스튜던트 t-검정으로 분석된 ±SEM으로, **p<0.01)
도 6은 Cdon을 결손시킨 혈관 평활근 세포를 석회화 배지에서 배양하여 석회화를 유도한 것을 알리자린 레드 염색으로 확인한 것이다. (Scale bar: 100μm)
도 7은 Cdon을 결손시킨 후 석회화가 유도된 혈관 평활근 세포(A7r5 세포)에서 골 형성 마커인 Runx2 및 ALPL의 상대적 mRNA 수준을 측정한 결과이다. (데이터는 스튜던트 t-검정으로 분석된 ±SEM으로, **p<0.01, ***p<0.005)
도 8은 shCdon을 포함한 렌티바이러스에 감염되어 Cdon이 결손된 혈관 평활근 세포(A7r5 세포)의 면역블롯 분석 결과이다.
도 9는 Cdon을 결손시킨 마우스(cKO)의 혈관 평활근에 VD3를 주입한 후, 석회화가 일어나는 면적과 골 형성 마커인 Runx2의 발현량을 각각 Von Kossa 염색과 면역형광 염색으로 확인한 것이다. (Scale bar: 100μm (위), 40μm (아래))
도 10은 Cdon을 결손시킨 마우스 모델과 정상군에 혈관 경화를 유도한 후, 맥파 전달속도(PWV)의 변화를 비교한 결과이다. (데이터는 스튜던트 t-검정으로 분석된 ±SEM으로, *p<0.05, ***p<0.005)
도 11은 Cdon (WT) 또는Ig2도메인이 제거된 Cdon(ΔIg2)을 발현시킨 혈관 평활근 세포에서 면역 블롯을 수행하여 b-Catenin과 Runx2의 발현을 분석한 결과이다.
도 12는 석회화 배지에 의해 석회화가 유도된 Cdon 또는 ΔIg2 발현 VSMC에서, Wnt 신호전달의 주요인자인 Axin2의 상대적 발현량을 나타낸 것이다. (데이터는 일원 분산 분석에 의해 분석된 ±SEM, n.s.=유의하지 않음, *p<0.05, **p<0.01)
도 13은 석회화 배지에 의해 석회화가 유도된 Cdon 또는 ΔIg2 발현 VSMC에서의 알리자린 레드 염색 이미지와 이를 정량화 한 그래프이다. (Scale bar: 100μm)
도 14는 Cdon-Fc 단백질(Cdon의 엑토도메인 전체가 Fc에 융합된 단백질)과 Ig2-Fc 단백질(Cdon-Ig2 도메인이 Fc에 융합된 단백질)을 나타낸 도이다.
도 15는 상기 도 14의 정제된 단백질이 함유된 석회화 배지에서 배양된 혈관 평활근 세포에서 b-Catenin과 Runx2의 발현을 면역블롯으로 분석한 결과이다.
도 16은 Cdon-Fc 또는 Ig2-Fc가 처리된 석회화 배지에서 배양된 혈관 평활근 세포의 알리자린 레드 염색 이미지 및 이를 정량화한 그래프를 나타낸 것이다. (데이터는 일원 분산 분석 테스트에 의해 분석된 ±SEM, ***p<0.005)
도 17은 Cdon-Fc 및 Ig2-Fc가 처리된 석회화 배지에서 배양된 혈관 평활근 세포에서 Wnt 신호전달 마커인 Axin2와 골 형성 마커인 Runx2, ALPL의 mRNA 발현량 차이를 나타낸 도이다. (데이터는 스튜던트 t-검정으로 분석된 ±SEM으로, *p<0.05, ***p<0.005)
이하, 본 명세서를 구체적으로 설명하기 위해 실시예를 들어 상세히 설명한다. 그러나, 본 명세서에 따른 실시예들은 여러 가지 다른 형태로 변형될 수 있으며, 본 명세서의 범위가 아래에서 상술하는 실시예들에 한정되는 것으로 해석되지는 않는다. 본 명세서의 실시예들은 당 업계에서 평균적인 지식을 가진 자에게 본 명세서를 보다 완전하게 설명하기 위해 제공되는 것이다.
실시예 1. Cdon-Ig2도메인 및 펩타이드 준비
1-1. 인간 또는 랫트로부터 유래된 Cdon-Ig2 도메인 분리 및 정제
본 발명의 Cdon은 UNIPROT Q4KMG0-1 (human) 또는 NCBI NP_059054.2 (Rat)으로부터 유래된 것이며, 이는 각각 서열번호 1 및 서열번호 2의 아미노산 서열로 나타낼 수 있다. 또한 본 발명의 Cdon-Ig2 도메인에 해당되는 부분은 상기 전체 Cdon 서열에 포함되는 것으로, 각각 서열번호 3(human 유래) 및 서열번호 4(rat 유래)의 아미노산 서열을 포함한다.
또한, Cdon-Fc 및 Ig2-Fc 융합 단백질을 각각 제조하기 위하여 Cdon의 재조합 단백질을 인간 IgG gamma의 Fc region과 결합하여 HEK293T 세포에 형질 감염하였다 (Cdon-Fc; Cdon의 엑토도메인 전체와 Fc의 융합 단백질, Cdon-Ig2-Fc; Cdon의 Ig2 domain과 Fc의 융합 단백질). 72시간 동안 형질 감염 후 HEK293T 세포를 2,000xg에서 10분 동안 원심 분리를 수행하고 상층액을 0.45um 필터 후, 상온에서 한 시간 동안 단백질 A 아가로즈 (Protein A agarose)와 반응시켰다. 단백질 A 아가로즈와 결합된 단백질은 0.1M 시트르산(pH 3.0)으로 용출하였으며, 이 용출된 단백질은 Amicon Ultra-4 centrifugal filter(MWCO 3K, Millipore)로 농축하여 사용하였다. 농축된 단백질의 순도와 온정성은 SDS-PAGE로 확인하였다.
1-2. 인간 또는 랫트로부터 유래된 Cdon-Ig2 도메인 분리 및 정제
랫트 유래 서열(서열번호 12)을 기반으로 Cdon-Ig2 도메인을 인공적으로 합성하였다. 합성된 도메인은 서열번호 5 내지 11의 아미노산 서열을 포함하며, 서열 정보는 하기 표 1과 같다. 또한, 합성된 Cdon-Ig2 도메인은 3차원 구조의 외부에 서열번호 7내지 10의 서열을 포함하고 있는 것을 확인하였다. 합성된 단백질의 3차원 구조를 도 1에 도시하였다.
| 위치 | 서열 | 서열번호 |
| Cdon-ig2 Ig strand A (120-123) | FDSS | 서열번호 5 |
| Cdon-ig2 Ig strand B (133-144) | KNTGFIGCRVPE | 서열번호 6 |
| Cdon-ig2 Ig strand C (149-155) | AEVRYKI | 서열번호 7 |
| Cdon-ig2 Ig strand D (157-160) | GKWL | 서열번호 8 |
| Cdon-ig2 Ig strand E (167-171) | YIILP | 서열번호 9 |
| Cdon-ig2 Ig strand F (173-179) | GNLQILN | 서열번호 10 |
| Cdon-ig2 Ig strand G (185-194) | KGSYKCAAYN | 서열번호 11 |
실시예 2. 세포 분리 및 배양
혈관 석회화를 유도하기 위한 마우스의 혈관 평활근 세포는 A7r5 세포주를 입수(ATCC, CRL-1444)하여 실험을 진행하였다. 또한, Cdon의 결손 실험을 위하여, 혈관 평활근 세포를 Cdon이 결손된 마우스로부터 직접 분리하였다. 6-8주령 랫트에서 혈관을 분리한 뒤에 콜라게나아제 용액 (0.2% Collagenase Type I, Elastase II, BSA, Trypsine inhibitor, 15 mM HEPES, Ham’s F12 medium)에 넣고 37℃에서 30분 동안 진탕 배양하였다. 상기 배양액을 정치시킨 후 내피세포를 긁어내고 외막을 벗겨낸 뒤에 dissection 배양액 (penicillin, streptomycin, Ham’s F12 media)에서 잘게 잘랐다. dissection 배양액을 버리고 다시 콜라게나아제 용액에 넣고 37℃에서 90분 동안 진탕 배양하였다. 상기 세포 상등액에 10%(v/v) 소태아혈청(FBS)을 포함한 DMEM을 첨가하여 콜라게나아제 반응을 중지시킨 뒤에 37℃ 배양기에서 배양하였고 다음날 10% FBS/DMEM 배지로 교체하여 세포를 배양하였다.
실험예 1. 혈관 세포의 석회화 유도가 Cdon 발현에 미치는 영향
혈관 평활근 세포에서 혈관 석회화를 유도하였을 때, Cdon의 발현량 변화를 확인하기 위하여 다음과 같은 실험을 진행하였다.
혈관 평활근 세포(VSMC)인 A7r5 세포에 석회화를 유도하기 위하여, 10mM β-글리세로포스페이트, 1mM 인슐린, 8mM CaCl2, 100nM 덱사메타손, 50mg/ml 아스코르빅산을 포함하는 석회화 배지(calcifying medium, CM)에서 배양하였다.
배양된 혈관 평활근 세포를 알리자린 레드 용액으로 염색하여, 칼슘의 생성, 즉 석회화가 유도되었는지 여부를 확인하였다. 도 2에서 보듯이, CM 배지에서 배양된 혈관 평활근 세포는 칼슘이 침착되어 석회화가 유도된 것을 확인하였으며, 골 분화 관련 마커인 Runx2와 ALPL의 mRNA발현이 증가된 것을 확인하였다(도 3). 그러나, Cdon의 발현은 대조군에 비하여 상대적으로 감소되었다(도 4). 이는 혈관 석회화가 유도된 경우, Cdon의 발현량이 감소되는 것을 보여주는 결과이다.
또한 실제 혈관에서 석회화 유도 시, Cdon및 αSMA의 발현량 변화를 확인하기 위하여 실험을 진행하였다. 마우스 대동맥 내 비타민 D3를 주입하여 석회화를 유도하고, 대동맥 내 Cdon/αSMA의 상대적 발현량을 면역 염색을 통하여 확인하였다.
그 결과 도 5 에서 보듯이, 정상 대동맥(Cont)에서 Cdon의 발현은 내측 평활근 부위 및 내피 세포 영역에서 높게 발현되나, VD3를 주입하여 석회화를 유발한 경우(VD3), 대동맥에서의 Cdon 단백질 및 전사체의 발현이 대조군 대비 급격히 감소된 것을 확인할 수 있었다.
실험예 2. Cdon의 결손에 따른 혈관 석회화 및 혈관 경화 악화
2-1) 혈관 평활근 세포에서의 석회화 유도
실시예 2와 같이 배양한 초대 배양 혈관 평활근 세포(VSMC)에서 Cdon 발현을 결손시키기 위하여, shCdon을 이용하였다. 이후, Cdon이 결손된 VSMC에 석회화를 유도하였다. αMEM, 2mM 오르토인산나트륨 및 10mM 글리세로포스페이트를 포함하는 석회화 배지(CM)에서 14일간 배양하였는데, 매 3일마다 배양액의 반을 새로 교체하였다. 그 결과, 도 6과 같이 shCdon으로 Cdon을 결손시킨 VSMC에서 석회화가 유도된 것을 확인하였다. 또한, 석회화를 확인할 수 있는 골 분화 마커인 Runx2, ALPL의 발현량 또한 대조군에 비해 Cdon 결손 세포에서 크게 증가된 것을 확인하였다 (도 7, 8).
2-2) 비타민 D3에 의한 대동맥 경화 유도
대동맥 경화가 유도된 동물 모델에서 Cdon 결손에 따른 효과를 확인하기 위한 실험을 수행하였다. 마우스의 혈관 평활근에서 Cdon을 결손시키기 위하여 10주령 마우스에 타목시펜(Tamoxifen, Tmx)을 주입하고 12주 경과 후, 정상 마우스와 Cdon cKO(conditional KO)에 13mg/kg의 용량으로 비타민 D3(VD3)를 3일 간격으로 3회 투여하여 혈관 경화를 유도하였다. 이후 각각의 마우스 모델의 대동맥 혈관에서의 맥파 전도속도(PWV), 골분화 마커의 발현량을 측정하여 비교하였다.
그 결과, 도 9에서 보듯이, Cdon이 결핍된 경우 VD3 에 의해 유도된 석회화 면적이 현저히 증가되었으며, 석회화와 관련된 골 형성 마커인 Runx2의 발현도 급격히 증가한 것을 확인할 수 있었다. 또한, 도 10에서 확인되는 바와 같이 혈관 경화를 유도한 경우 맥파 전도속도(PWV)가 다소 증가되었는데, Cdon 결실 마우스에서 PWV의 증가가 더욱 두드러지게 확인되었다.
실험예 3. Cdon-Ig2 결손이 혈관 석회화에 끼치는 영향
상기 실시예 2-1과 같이 초대 배양 혈관 평활근 세포인 A7r5 세포에 Cdon WT 또는 Ig2 domain이 결손된 돌연변이 Cdon(ΔIg2)을 형질 감염한 후 CM을 처리하여 석회화를 유도하였다.
그 결과 도 11에서 보듯이, Cdon WT를 형질 감염한 경우, β-Catenin 및 Runx2의 발현이 감소되었으나, Ig2 domain 결손 돌연변이를 형질 감염한 경우 β-Catenin 및 Runx2이 대조군과 거의 동등한 수준으로 발현된 것을 확인하였다. 또한 도 12와 같이, Wnt 신호 전달 경로의 핵심인자인 Axin2의 발현도 Cdon WT를 형질 감염한 경우에는 감소하였으나, Ig2 domain 결손 돌연변이를 형질 감염한 경우에는 발현이 유지되었다. 즉, CM으로 석회화를 유도한 경우 Cdon WT를 형질 감염한 경우에는 석회화가 유의적으로 감소된 것을 확인하였으나, Ig2 domain 결손 돌연변이를 형질 감염한 경우에는 석회화를 저해하지 못하였다 (도 13).
실험예 4. Cdon-Ig2 발현에 의한 석회화 감소 효과
Cdon-Ig2에 의한 혈관 석회화 치료 효과를 확인하기 위하여, 상기 실시예 2-1과 같이 초대 배양 혈관 평활근 세포인 A7r5 세포에 Cdon-Fc와 Ig2-Fc를 각각 형질 감염(도 14)한 후, 석회화 배지에서 상기 실험예 2와 같은 방법으로 배양하여 석회화를 유도하고 석회화에 대한 영향을 확인하였다.
그 결과, 도 15에서 보듯이, Cdon-Fc 및 Ig2-Fc를 형질 감염한 경우, 대조군에 비해 β-Catenin 및 Runx2의 발현 유도가 억제되었다. 또한, 상기 효과는 IgG에 의한 것이 아니며, Cdon 및 Cdon-Ig2 도메인에 의한 것임을 도 16과 같이 알리자린 레드 염색 결과로부터 확인하였다. 또한, Cdon 및 Cdon-Ig2 도메인이 석회화 배지에 의한 골 형성 유전자의 유도 및 Wnt 신호 전달 경로의 활성화를 억제하는 것을 골 분화 마커인 Runx2, ALPL의 발현량과 Wnt 신호전달 인자 Axin2의 발현량을 분석하여 도 17과 같이 확인하였다. 상기 결과로부터 Cdon-Ig2 도메인의 발현을 통해 혈관 세포에서의 석회화를 감소시킬 수 있다는 것을 확인하였다.
이제까지 본 발명에 대하여 그 바람직한 실시예들을 중심으로 살펴보았다. 본 발명이 속하는 기술 분야에서 통상의 지식을 가진 자는 본 발명이 본 발명의 본질적인 특성에서 벗어나지 않는 범위에서 변형된 형태로 구현될 수 있음을 이해할 수 있을 것이다. 그러므로 개시된 실시예들은 한정적인 관점이 아니라 설명적인 관점에서 고려되어야 한다. 본 발명의 범위는 전술한 설명이 아니라 청구범위에 나타나 있으며, 그와 동등한 범위 내에 있는 모든 차이점은 본 발명에 포함된 것으로 해석되어야 할 것이다.
<110> Animuscure Inc.
<120> A pharmaceutical composition comprising Cdon-Ig2 domain for
treating vascular calcification
<130> PDPC214511
<160> 12
<170> KoPatentIn 3.0
<210> 1
<211> 1288
<212> PRT
<213> Artificial Sequence
<220>
<223> Human Cdon sequence
<400> 1
Met His Pro Asp Leu Gly Pro Leu Cys Thr Leu Leu Tyr Val Thr Leu
1 5 10 15
Thr Ile Leu Cys Ser Ser Val Ser Ser Asp Leu Ala Pro Tyr Phe Thr
20 25 30
Ser Glu Pro Leu Ser Ala Val Gln Lys Leu Gly Gly Pro Val Val Leu
35 40 45
His Cys Ser Ala Gln Pro Val Thr Thr Arg Ile Ser Trp Leu His Asn
50 55 60
Gly Lys Thr Leu Asp Gly Asn Leu Glu His Val Ile Lys Ile His Gln
65 70 75 80
Gly Thr Leu Thr Ile Leu Ser Leu Asn Ser Ser Leu Leu Gly Tyr Tyr
85 90 95
Gln Cys Leu Ala Asn Asn Ser Ile Gly Ala Ile Val Ser Gly Pro Ala
100 105 110
Thr Val Ser Val Ala Val Leu Gly Asp Phe Gly Ser Ser Thr Lys His
115 120 125
Val Ile Thr Ala Glu Glu Lys Ser Ala Gly Phe Ile Gly Cys Arg Val
130 135 140
Pro Glu Ser Asn Pro Lys Ala Glu Val Arg Tyr Lys Ile Arg Gly Lys
145 150 155 160
Trp Leu Glu His Ser Thr Glu Asn Tyr Leu Ile Leu Pro Ser Gly Asn
165 170 175
Leu Gln Ile Leu Asn Val Ser Leu Glu Asp Lys Gly Ser Tyr Lys Cys
180 185 190
Ala Ala Tyr Asn Pro Val Thr His Gln Leu Lys Val Glu Pro Ile Gly
195 200 205
Arg Lys Leu Leu Val Ser Arg Pro Ser Ser Asp Asp Val His Ile Leu
210 215 220
His Pro Thr His Ser Gln Ala Leu Ala Val Leu Ser Arg Ser Pro Val
225 230 235 240
Thr Leu Glu Cys Val Val Ser Gly Val Pro Ala Pro Gln Val Tyr Trp
245 250 255
Leu Lys Asp Gly Gln Asp Ile Ala Pro Gly Ser Asn Trp Arg Arg Leu
260 265 270
Tyr Ser His Leu Ala Thr Asp Ser Val Asp Pro Ala Asp Ser Gly Asn
275 280 285
Tyr Ser Cys Met Ala Gly Asn Lys Ser Gly Asp Val Lys Tyr Val Thr
290 295 300
Tyr Met Val Asn Val Leu Glu His Ala Ser Ile Ser Lys Gly Leu Gln
305 310 315 320
Asp Gln Ile Val Ser Leu Gly Ala Thr Val His Phe Thr Cys Asp Val
325 330 335
His Gly Asn Pro Ala Pro Asn Cys Thr Trp Phe His Asn Ala Gln Pro
340 345 350
Ile His Pro Ser Ala Arg His Leu Thr Ala Gly Asn Gly Leu Lys Ile
355 360 365
Ser Gly Val Thr Val Glu Asp Val Gly Met Tyr Gln Cys Val Ala Asp
370 375 380
Asn Gly Ile Gly Phe Met His Ser Thr Gly Arg Leu Glu Ile Glu Asn
385 390 395 400
Asp Gly Gly Phe Lys Pro Val Ile Ile Thr Ala Pro Val Ser Ala Lys
405 410 415
Val Ala Asp Gly Asp Phe Val Thr Leu Ser Cys Asn Ala Ser Gly Leu
420 425 430
Pro Val Pro Val Ile Arg Trp Tyr Asp Ser His Gly Leu Ile Thr Ser
435 440 445
His Pro Ser Gln Val Leu Arg Ser Lys Ser Arg Lys Ser Gln Leu Ser
450 455 460
Arg Pro Glu Gly Leu Asn Leu Glu Pro Val Tyr Phe Val Leu Ser Gln
465 470 475 480
Ala Gly Ala Ser Ser Leu His Ile Gln Ala Val Thr Gln Glu His Ala
485 490 495
Gly Lys Tyr Ile Cys Glu Ala Ala Asn Glu His Gly Thr Thr Gln Ala
500 505 510
Glu Ala Ser Leu Met Val Val Pro Phe Glu Thr Asn Thr Lys Ala Glu
515 520 525
Thr Val Thr Leu Pro Asp Ala Ala Gln Asn Asp Asp Arg Ser Lys Arg
530 535 540
Asp Gly Ser Glu Thr Gly Leu Leu Ser Ser Phe Pro Val Lys Val His
545 550 555 560
Pro Ser Ala Val Glu Ser Ala Pro Glu Lys Asn Ala Ser Gly Ile Ser
565 570 575
Val Pro Asp Ala Pro Ile Ile Leu Ser Pro Pro Gln Thr His Thr Pro
580 585 590
Asp Thr Tyr Asn Leu Val Trp Arg Ala Gly Lys Asp Gly Gly Leu Pro
595 600 605
Ile Asn Ala Tyr Phe Val Lys Tyr Arg Lys Leu Asp Asp Gly Val Gly
610 615 620
Met Leu Gly Ser Trp His Thr Val Arg Val Pro Gly Ser Glu Asn Glu
625 630 635 640
Leu His Leu Ala Glu Leu Glu Pro Ser Ser Leu Tyr Glu Val Leu Met
645 650 655
Val Ala Arg Ser Ala Ala Gly Glu Gly Gln Pro Ala Met Leu Thr Phe
660 665 670
Arg Thr Ser Lys Glu Lys Thr Ala Ser Ser Lys Asn Thr Gln Ala Ser
675 680 685
Ser Pro Pro Val Gly Ile Pro Lys Tyr Pro Val Val Ser Glu Ala Ala
690 695 700
Asn Asn Asn Phe Gly Val Val Leu Thr Asp Ser Ser Arg His Ser Gly
705 710 715 720
Val Pro Glu Ala Pro Asp Arg Pro Thr Ile Ser Thr Ala Ser Glu Thr
725 730 735
Ser Val Tyr Val Thr Trp Ile Pro Arg Ala Asn Gly Gly Ser Pro Ile
740 745 750
Thr Ala Phe Lys Val Glu Tyr Lys Arg Met Arg Thr Ser Asn Trp Leu
755 760 765
Val Ala Ala Glu Asp Ile Pro Pro Ser Lys Leu Ser Val Glu Val Arg
770 775 780
Ser Leu Glu Pro Gly Ser Thr Tyr Lys Phe Arg Val Ile Ala Ile Asn
785 790 795 800
His Tyr Gly Glu Ser Phe Arg Ser Ser Ala Ser Arg Pro Tyr Gln Val
805 810 815
Val Gly Phe Pro Asn Arg Phe Ser Ser Arg Pro Ile Thr Gly Pro His
820 825 830
Ile Ala Tyr Thr Glu Ala Val Ser Asp Thr Gln Ile Met Leu Lys Trp
835 840 845
Thr Tyr Ile Pro Ser Ser Asn Asn Asn Thr Pro Ile Gln Gly Phe Tyr
850 855 860
Ile Tyr Tyr Arg Pro Thr Asp Ser Asp Asn Asp Ser Asp Tyr Lys Arg
865 870 875 880
Asp Val Val Glu Gly Ser Lys Gln Trp His Met Ile Gly His Leu Gln
885 890 895
Pro Glu Thr Ser Tyr Asp Ile Lys Met Gln Cys Phe Asn Glu Gly Gly
900 905 910
Glu Ser Glu Phe Ser Asn Val Met Ile Cys Glu Thr Lys Val Lys Arg
915 920 925
Val Pro Gly Ala Ser Glu Tyr Pro Val Lys Asp Leu Ser Thr Pro Pro
930 935 940
Asn Ser Leu Gly Ser Gly Gly Asn Val Gly Pro Ala Thr Ser Pro Ala
945 950 955 960
Arg Ser Ser Asp Met Leu Tyr Leu Ile Val Gly Cys Val Leu Gly Val
965 970 975
Met Val Leu Ile Leu Met Val Phe Ile Ala Met Cys Leu Trp Lys Asn
980 985 990
Arg Gln Gln Asn Thr Ile Gln Lys Tyr Asp Pro Pro Gly Tyr Leu Tyr
995 1000 1005
Gln Gly Ser Asp Met Asn Gly Gln Met Val Asp Tyr Thr Thr Leu Ser
1010 1015 1020
Gly Ala Ser Gln Ile Asn Gly Asn Val His Gly Gly Phe Leu Thr Asn
1025 1030 1035 1040
Gly Gly Leu Ser Ser Gly Tyr Ser His Leu His His Lys Val Pro Asn
1045 1050 1055
Ala Val Asn Gly Ile Val Asn Gly Ser Leu Asn Gly Gly Leu Tyr Ser
1060 1065 1070
Gly His Ser Asn Ser Leu Thr Arg Thr His Val Asp Phe Glu His Pro
1075 1080 1085
His His Leu Val Asn Gly Gly Gly Met Tyr Thr Ala Val Pro Gln Ile
1090 1095 1100
Asp Pro Leu Glu Cys Val Asn Cys Arg Asn Cys Arg Asn Asn Asn Arg
1105 1110 1115 1120
Cys Phe Thr Lys Thr Asn Ser Thr Phe Ser Ser Ser Pro Pro Pro Val
1125 1130 1135
Val Pro Val Val Ala Pro Tyr Pro Gln Asp Gly Leu Glu Met Lys Pro
1140 1145 1150
Leu Ser His Val Lys Val Pro Val Cys Leu Thr Ser Ala Val Pro Asp
1155 1160 1165
Cys Gly Gln Leu Pro Glu Glu Ser Val Lys Asp Asn Val Glu Pro Val
1170 1175 1180
Pro Thr Gln Arg Thr Cys Cys Gln Asp Ile Val Asn Asp Val Ser Ser
1185 1190 1195 1200
Asp Gly Ser Glu Asp Pro Ala Glu Phe Ser Arg Gly Gln Glu Gly Met
1205 1210 1215
Ile Asn Leu Arg Ile Pro Asp His Leu Gln Leu Ala Lys Ser Cys Val
1220 1225 1230
Trp Glu Gly Asp Ser Cys Ala His Ser Glu Thr Glu Ile Asn Ile Val
1235 1240 1245
Ser Trp Asn Ala Leu Ile Leu Pro Pro Val Pro Glu Gly Cys Ala Glu
1250 1255 1260
Lys Thr Met Trp Ser Pro Pro Gly Ile Pro Leu Asp Ser Pro Thr Glu
1265 1270 1275 1280
Val Leu Gln Gln Pro Arg Glu Thr
1285
<210> 2
<211> 1256
<212> PRT
<213> Artificial Sequence
<220>
<223> Rat Cdon sequence
<400> 2
Met His Pro Asp Leu Gly Pro Leu Trp Lys Leu Leu Tyr Val Leu Val
1 5 10 15
Ile Leu Cys Ser Ser Val Ser Ser Asp Leu Ala Pro Tyr Phe Ile Ser
20 25 30
Glu Pro Leu Ser Ala Val Gln Lys Leu Gly Arg Pro Val Val Leu His
35 40 45
Cys Ser Ala Lys Pro Val Thr Ala Arg Ile Ser Trp Leu His Asn Gly
50 55 60
Lys Arg Leu Asp Arg Asn Thr Glu Gln Ile Lys Ile His Arg Gly Thr
65 70 75 80
Leu Thr Ile Leu Ser Leu Asn Pro Ser Leu Ser Gly Cys Tyr Gln Cys
85 90 95
Val Ala Asn Asn Ser Val Gly Ala Val Val Ser Gly Pro Ala Thr Val
100 105 110
Ser Ala Ala Ala Leu Ala Asp Phe Asp Ser Ser Thr Met His Val Ile
115 120 125
Thr Ala Glu Glu Lys Asn Thr Gly Phe Ile Gly Cys Arg Val Pro Glu
130 135 140
Ser Asn Pro Lys Ala Glu Val Arg Tyr Lys Ile Arg Gly Lys Trp Leu
145 150 155 160
Met Tyr Ser Thr Gly Asn Tyr Ile Ile Leu Pro Ser Gly Asn Leu Gln
165 170 175
Ile Leu Asn Val Ser Ser Lys Asp Lys Gly Ser Tyr Lys Cys Ala Ala
180 185 190
Tyr Asn Pro Val Thr Ser Glu Leu Lys Val Glu Pro Ala Gly Arg Lys
195 200 205
Leu Leu Val Ser Arg Pro Ser Ser Asp Gly Phe His Ile Leu His Pro
210 215 220
Ala Leu Ser Gln Ala Leu Ala Val Leu Pro His Ser Pro Val Thr Leu
225 230 235 240
Glu Cys Val Val Ser Gly Val Pro Ala Ser Gln Val Tyr Trp Leu Lys
245 250 255
Asp Gly Gln Asp Ala Leu Ser Gly Ser Asn Trp Arg Arg Leu Tyr Ser
260 265 270
His Leu Ala Thr Ala Ser Ile Asp Pro Ala Asp Ser Gly Asn Tyr Ser
275 280 285
Cys Val Val Gly Asn Asn Arg Ser Gly Asp Val Lys His Val Thr Tyr
290 295 300
Thr Val Asn Val Leu Glu His Ala Ser Ile Ser Lys Gly Leu His Asp
305 310 315 320
Gln Lys Val Ser Leu Gly Ala Thr Val Arg Phe Thr Cys Glu Val His
325 330 335
Gly Asn Pro Ala Pro Asn Arg Thr Trp Phe His Asn Ala Gln Pro Ile
340 345 350
Arg Pro Ser Ser Arg His Leu Thr Glu Gly Ser Val Leu Lys Ile Thr
355 360 365
Gly Val Ile Met Glu Asp Ser Gly Leu Tyr Gln Cys Met Ala Asp Asn
370 375 380
Gly Ile Gly Phe Met Gln Ser Thr Gly Arg Leu Gln Ile Glu Gln Asp
385 390 395 400
Ser Gly Gln Arg Pro Val Ile Val Thr Ala Pro Ala Asn Val Glu Val
405 410 415
Thr Asp Gly Asp Phe Val Thr Leu Ser Cys Asn Ala Thr Gly Glu Pro
420 425 430
Val Pro Val Ile His Trp Tyr Gly Arg His Gly Leu Ile Thr Ser His
435 440 445
Pro Ser Gln Val Leu Arg Ser Lys Ser Arg Lys Ser His Leu Phe Arg
450 455 460
Pro Gly Asp Leu Asp Pro Glu Pro Val Tyr Leu Ile Met Ser Gln Ala
465 470 475 480
Gly Ser Ser Ser Leu Ser Ile Gln Ala Val Thr Trp Glu His Ala Gly
485 490 495
Lys Tyr Thr Cys Glu Ala Val Asn Lys His Gly Ser Thr Gln Ser Glu
500 505 510
Ala Phe Leu Thr Val Val Pro Phe Glu Thr Asn Thr Lys Ala Glu Pro
515 520 525
Val Thr Pro Ser Glu Ala Ser Gln Asn Asp Glu Arg Asp Pro Arg Asp
530 535 540
Gly Ser Glu Ser Gly Leu Leu Asn Leu Phe Pro Val Lys Val His Ser
545 550 555 560
Gly Gly Val Glu Leu Pro Ala Glu Lys Asn Ala Ser Val Pro Asp Ala
565 570 575
Pro Asn Ile Leu Ser Pro Pro Gln Thr His Met Pro Asp Thr Tyr Thr
580 585 590
Leu Val Trp Arg Ala Gly Arg Asp Gly Gly Met Pro Ile Asn Ala Tyr
595 600 605
Phe Val Lys Tyr Arg Lys Leu Asp Asp Gly Ser Gly Ala Val Gly Ser
610 615 620
Trp His Thr Val Arg Val Pro Gly Ser Glu Ser Glu Leu His Leu Thr
625 630 635 640
Glu Leu Glu Pro Ser Ser Leu Tyr Glu Val Leu Met Val Ala Arg Ser
645 650 655
Ala Val Gly Glu Gly Gln Pro Ala Met Leu Thr Phe Arg Thr Ser Lys
660 665 670
Glu Lys Met Ala Ser Ser Lys Asn Thr Gln Ala Ser Phe Pro Pro Val
675 680 685
Gly Ile Pro Lys Arg Pro Val Thr Ser Glu Ala Ser Asn Ser Asn Phe
690 695 700
Gly Val Val Leu Thr Asp Ser Ser Arg His Ser Gly Val Pro Glu Ala
705 710 715 720
Pro Asp Arg Pro Thr Ile Ser Met Ala Ser Glu Thr Ser Val Tyr Val
725 730 735
Thr Trp Ile Pro Arg Ala Asn Gly Gly Ser Pro Ile Thr Ala Phe Lys
740 745 750
Val Glu Tyr Lys Arg Met Lys Ser Ser Asp Trp Leu Val Ala Ala Glu
755 760 765
Asp Ile Pro Pro Ser Lys Leu Ser Val Glu Val Arg Ser Leu Glu Pro
770 775 780
Gly Ser Ile Tyr Lys Phe Arg Val Ile Ala Ile Asn His Tyr Gly Glu
785 790 795 800
Ser Phe Arg Ser Ser Ala Ser Arg Pro Tyr Gln Val Ala Gly Phe Pro
805 810 815
Asn Arg Phe Ser Asn Arg Pro Ile Thr Gly Pro His Ile Ala Tyr Thr
820 825 830
Glu Ala Val Ser Asp Thr Gln Ile Met Leu Lys Trp Thr Tyr Ile Pro
835 840 845
Ser Ser Asn Asn Asn Thr Pro Ile Gln Gly Phe Tyr Ile Tyr Tyr Arg
850 855 860
Pro Thr Asp Ser Asp Asn Asp Ser Asp Tyr Lys Arg Asp Val Val Glu
865 870 875 880
Gly Ser Lys Gln Trp His Thr Ile Gly His Leu Gln Pro Glu Thr Ser
885 890 895
Tyr Asp Ile Lys Met Gln Cys Phe Asn Glu Gly Gly Glu Ser Glu Phe
900 905 910
Ser Asn Val Met Ile Cys Glu Thr Lys Val Lys Arg Val Pro Gly Ala
915 920 925
Ser Glu Tyr Pro Met Lys Glu Leu Ser Thr Pro Pro Ser Ser Ser Gly
930 935 940
Asn Gly Gly Asn Val Gly Pro Ala Thr Ser Pro Ala Arg Ser Ser Asp
945 950 955 960
Met Leu Tyr Leu Ile Val Gly Cys Val Leu Gly Val Met Val Leu Ile
965 970 975
Leu Leu Val Phe Ile Ala Leu Cys Leu Trp Lys Ser Arg Gln Gln Ser
980 985 990
Ala Ile Gln Lys Tyr Asp Pro Pro Gly Tyr Leu Tyr Gln Gly Ser Glu
995 1000 1005
Ile Asn Gly Gln Met Val Glu Tyr Thr Thr Leu Ser Gly Thr Ala Arg
1010 1015 1020
Ile Asn Gly Ser Val His Gly Gly Phe Leu Ser Lys Gly Ser Leu Ser
1025 1030 1035 1040
Asn Gly Cys Ser His Leu His His Lys Gly Pro Asn Gly Val Asn Gly
1045 1050 1055
Ile Leu Asn Gly Thr Ile Asn Gly Gly Leu Tyr Ser Ala His Thr Ser
1060 1065 1070
Ser Leu Thr Arg Thr Cys Val Glu Phe Glu His Pro His His Leu Val
1075 1080 1085
Asn Gly Gly Ala Val Tyr Thr Ala Val Pro Gln Met Asp Pro Leu Glu
1090 1095 1100
Cys Ile Asn Cys Arg Asn Cys Arg Asn Asn Asn Arg Cys Phe Thr Lys
1105 1110 1115 1120
Thr Asn Ser Pro Leu Pro Val Val Pro Val Val Ala Ser Tyr Pro Gln
1125 1130 1135
Asp Gly Leu Glu Met Lys Pro Leu Gly Val Met Lys Phe Pro Val Cys
1140 1145 1150
Pro Val Ser Thr Val Pro Asp Gly Gly Gln Ile Pro Glu Glu Cys Leu
1155 1160 1165
Lys Asp Ser Val Ala Pro Ala Pro Thr Gln Arg Thr Cys Arg Gln Asp
1170 1175 1180
Asn Thr Ser Asp Ile Asn Ser Asp Ser Thr Glu Asp Thr Ala Glu Phe
1185 1190 1195 1200
Asn Arg Gly Asp Ser Ser Gly His Ser Glu Ala Glu Asp Lys Val Phe
1205 1210 1215
Ser Trp Ser Pro Leu Ile Leu Ser Pro Val Leu Glu Asp Cys Ser Glu
1220 1225 1230
Lys Thr Ala Trp Ser Pro Pro Gly Pro Pro Leu Asp Gly Leu Ser Val
1235 1240 1245
Val Leu Gln Gln Ala Gln Glu Thr
1250 1255
<210> 3
<211> 94
<212> PRT
<213> Artificial Sequence
<220>
<223> Human Cdon-ig2 domain sequence
<400> 3
Ala Thr Val Ser Val Ala Val Leu Gly Asp Phe Gly Ser Ser Thr Lys
1 5 10 15
His Val Ile Thr Ala Glu Glu Lys Ser Ala Gly Phe Ile Gly Cys Arg
20 25 30
Val Pro Glu Ser Asn Pro Lys Ala Glu Val Arg Tyr Lys Ile Arg Gly
35 40 45
Lys Trp Leu Glu His Ser Thr Glu Asn Tyr Leu Ile Leu Pro Ser Gly
50 55 60
Asn Leu Gln Ile Leu Asn Val Ser Leu Glu Asp Lys Gly Ser Tyr Lys
65 70 75 80
Cys Ala Ala Tyr Asn Pro Val Thr His Gln Leu Lys Val Glu
85 90
<210> 4
<211> 86
<212> PRT
<213> Artificial Sequence
<220>
<223> Rat Cdon-ig2 domain sequence
<400> 4
Thr Val Ser Ala Ala Ala Leu Ala Asp Phe Asp Ser Ser Thr Met His
1 5 10 15
Val Ile Thr Ala Glu Glu Lys Asn Thr Gly Phe Ile Gly Cys Arg Val
20 25 30
Pro Glu Ser Asn Pro Lys Ala Glu Val Arg Tyr Lys Ile Arg Gly Lys
35 40 45
Trp Leu Met Tyr Ser Thr Gly Asn Tyr Ile Ile Leu Pro Ser Gly Asn
50 55 60
Leu Gln Ile Leu Asn Val Ser Ser Lys Asp Lys Gly Ser Tyr Lys Cys
65 70 75 80
Ala Ala Tyr Asn Pro Val
85
<210> 5
<211> 4
<212> PRT
<213> Artificial Sequence
<220>
<223> Cdon-Ig2 Ig strand A (120-123)
<400> 5
Phe Asp Ser Ser
1
<210> 6
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> Cdon-Ig2 Ig strand B (133-144)
<400> 6
Lys Asn Thr Gly Phe Ile Gly Cys Arg Val Pro Glu
1 5 10
<210> 7
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> Cdon-Ig2 Ig strand C (149-155)
<400> 7
Ala Glu Val Arg Tyr Lys Ile
1 5
<210> 8
<211> 4
<212> PRT
<213> Artificial Sequence
<220>
<223> Cdon-Ig2 Ig strand D (157-160)
<400> 8
Gly Lys Trp Leu
1
<210> 9
<211> 5
<212> PRT
<213> Artificial Sequence
<220>
<223> Cdon-Ig2 Ig strand E (167-171)
<400> 9
Tyr Ile Ile Leu Pro
1 5
<210> 10
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> Cdon-Ig2 Ig strand F (173-179)
<400> 10
Gly Asn Leu Gln Ile Leu Asn
1 5
<210> 11
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> Cdon-Ig2 Ig strand G (185-194)
<400> 11
Lys Gly Ser Tyr Lys Cys Ala Ala Tyr Asn
1 5 10
<210> 12
<211> 125
<212> PRT
<213> Artificial Sequence
<220>
<223> Rat Ig2 domain (artificial)
<400> 12
Phe Asp Ser Ser Thr Met His Val Ile Thr Ala Glu Glu Lys Asn Thr
1 5 10 15
Gly Phe Ile Gly Cys Arg Val Pro Glu Ser Asn Pro Lys Ala Glu Val
20 25 30
Arg Tyr Lys Ile Arg Gly Lys Trp Leu Met Tyr Ser Thr Gly Asn Tyr
35 40 45
Ile Ile Leu Pro Ser Gly Asn Leu Gln Ile Leu Asn Val Ser Ser Lys
50 55 60
Asp Lys Gly Ser Tyr Lys Cys Ala Ala Tyr Asn Pro Val Lys Asn Thr
65 70 75 80
Gly Phe Ile Gly Cys Arg Val Pro Glu Ser Asn Pro Lys Ala Glu Val
85 90 95
Arg Tyr Lys Ile Arg Gly Lys Trp Leu Met Tyr Ser Thr Gly Asn Tyr
100 105 110
Ile Ile Leu Pro Ser Gly Asn Leu Gln Ile Leu Asn Val
115 120 125
Claims (11)
- Cdon-Ig2 도메인 또는 이로부터 유래되는 펩타이드를 포함하는, 혈관 석회화 또는 혈관 석회화와 관련된 혈관 질환의 예방 또는 치료용 약학적 조성물.
- Cdon-Ig2 도메인 또는 이로부터 유래한 펩타이드를 암호화하는 폴리뉴클레오티드를 포함하는 벡터, 또는 상기 벡터를 포함하는 세포를 포함하는 혈관 석회화 또는 혈관 질환의 예방 또는 치료용 조성물.
- Cdon-Ig2 도메인 또는 이로부터 유래되는 펩타이드를 포함하는, 혈관 석회화 또는 혈관 석회화와 관련된 혈관 질환의 예방 또는 개선용 건강기능식품 조성물.
- Cdon-Ig2 도메인 또는 이로부터 유래한 펩타이드를 암호화하는 폴리뉴클레오티드를 포함하는 벡터, 또는 상기 벡터를 포함하는 세포를 포함하는 혈관 석회화 또는 혈관 질환의 예방 또는 개선용 건강기능식품 조성물.
- 제1항 내지 제4항 중 어느 한 항에 있어서,
상기 Cdon-Ig2 도메인 또는 이로부터 유래되는 펩타이드는 서열번호 1 내지 4의 아미노산 서열 중 선택되는 어느 하나, 또는 서열번호 5 내지 11의 아미노산 서열 중 하나 이상의 아미노산 서열을 포함하는 펩타이드를 포함하는 것인 혈관 석회화 또는 혈관 질환의 예방 또는 치료용 조성물. - 제1항 내지 제4항 중 어느 한 항에 있어서,
상기 혈관 석회화와 관련된 질환은 심근 경색, 혈관(동맥)경화, 고혈압, 허혈성 심장 질환, 관류 장애, 심장 비대증, 좌심실 비대증, 심근 허혈, 말초 동맥 허혈 및 심부전으로 이루어진 군으로부터 선택되는 것인 혈관 석회화 또는 혈관 질환의 예방 또는 치료용 조성물. - 제2항 또는 제4항에 있어서,
상기 벡터는 선형 DNA, 플라스미드 DNA 또는 재조합 바이러스성 벡터인 것을 특징으로 하는 혈관 석회화 또는 혈관 질환의 예방 또는 치료용 조성물. - 제7항에 있어서,
상기 재조합 바이러스성 벡터는 레트로 바이러스, 아데노 바이러스, 아데노 부속 바이러스, 헤르페스 심플렉스 바이러스, 렌티바이러스로 구성되는 군으로부터 선택되는 어느 하나인 것을 특징으로 하는 암 예방 및 치료용 약학적 혈관 석회화 또는 혈관 질환의 예방 또는 치료용 조성물. - 제2항 또는 제4항 중 어느 한 항에 있어서,
상기 세포는 혈관 근육세포, 혈관 평활근 세포, 혈관 내피세포, 혈관모세포 또는 혈관 줄기세포 중 선택되는 어느 하나인 것인 혈관 석회화 또는 혈관 질환의 예방 또는 치료용 조성물. - 1)실험군으로서 피검체 유래 시료에서 Cdon-Ig2 도메인 또는 이로부터 유래한 펩타이드의 발현량을 측정하는 단계;
2)상기 Cdon-Ig2 도메인 또는 이로부터 유래한 펩타이드의 발현량과 대조군으로서 정상 개체 유래 시료의 Cdon-Ig2 도메인 또는 이로부터 유래한 펩타이드의 발현량을 비교하는 단계; 및
3) Cdon-Ig2 도메인 또는 이로부터 유래한 펩타이드의 발현량이 대조군에 비해 감소하는 경우 혈관 석회화 또는 이와 관련된 혈관 질환에 걸릴 위험이 높은 것으로 판정하는 단계를 포함하는, 혈관 석회화 또는 혈관 질환에 대한 정보를 제공하기 위한 방법. - 제10항에 있어서,
상기 1)단계의 펩타이드 발현량은 웨스턴블랏(Western blotting), 실시간 중합효소 연쇄반응(qRT-PCR), 효소-면역화학 검출법(Enzyme-linked immunosorbent assay, ELISA), 면역조직화학 염색법(immunohistochemical staining), 면역침강(immunoprecipitation) 및 면역 형광법(immunofluorescence)으로 구성된 군으로부터 선택되는 어느 하나의 방법으로 검출하는 것을 특징으로 하는 혈관 석회화 또는 혈관 질환에 대한 정보를 제공하기 위한 방법.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR1020220052520A KR20230152945A (ko) | 2022-04-28 | 2022-04-28 | Cdon-Ig2 도메인 단백질을 포함하는 혈관 석회화 치료용 조성물 |
| PCT/KR2023/005555 WO2023211094A1 (ko) | 2022-04-28 | 2023-04-24 | Cdon-ig2 도메인 단백질을 포함하는 혈관 석회화 치료용 조성물 |
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| KR1020220052520A KR20230152945A (ko) | 2022-04-28 | 2022-04-28 | Cdon-Ig2 도메인 단백질을 포함하는 혈관 석회화 치료용 조성물 |
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| EP2925363A4 (en) * | 2012-11-29 | 2016-11-09 | Strasspharma Llc | METHOD FOR MODULATING FOLLICLE-STIMULATING HORMONACTIVITY |
| WO2020167927A1 (en) * | 2019-02-15 | 2020-08-20 | Institute For Cancer Research D/B/A The Research Institute Of Fox Chase Cancer Center | Antibodies to cell adhesion molecule-related/down-regulated by oncogenes (cdon) and uses thereof |
| JP2023519926A (ja) * | 2020-03-23 | 2023-05-15 | キュリジン カンパニー，リミテッド | 二重特異性核酸分子を含む抗癌ウイルスの構造 |
| EP4132954A1 (en) * | 2020-04-08 | 2023-02-15 | Institut National de la Santé et de la Recherche Médicale (INSERM) | Use of cdon inhibitors for the treatment of endothelial dysfunction |
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