KR20200018955A - Grp75 단백질을 유효성분으로 포함하는 신경 손상 질환 예방 또는 치료용 조성물 - Google Patents
Grp75 단백질을 유효성분으로 포함하는 신경 손상 질환 예방 또는 치료용 조성물 Download PDFInfo
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Abstract
본 발명은 글루코스-관련 단백질 75(Glucose-related protein 75; Grp75) 단백질을 유효성분으로 포함하는 신경 손상 질환 예방 또는 치료용 조성물에 관한 것으로서, Grp75 단백질의 과발현이 소포체로부터의 미토콘드리아로의 칼슘 이동을 활성화 시켜, 신경재생에 기본적으로 필요한 에너지를 더 생성하게 만드는 것을 확인하였으며, 세포 배양에서 Grp75 단백질 과발현이 신경 재생을 촉진하는 것을 확인하였다. 이에, Grp75 단백질은 중추 신경 및 말초 신경 손상 치료제 개발에 유용하게 활용될 수 있을 것으로 기대된다.
Description
본 발명은 글루코스-관련 단백질 75(Glucose-related protein 75; Grp75) 단백질을 유효성분으로 포함하는 신경 손상 질환 예방 또는 치료용 조성물에 관한 것이다.
소포체와 미토콘드리아는 세포 내에서 많은 부분을 차지하며 주요한 역할들을 수행한다. 소포체는 분비 단백질 합성, 칼슘 이온 항상성 조절, 지질 합성 등을 담당하며 미토콘드리아는 세포가 사용하는 에너지를 합성하는 역할을 담당하고 있다. 각각의 기능도 중요하지만, 소포체와 미토콘드리아는 접촉막을 형성하고 소통을 통해 서로의 기능을 조절하기도 한다. 두 세포 소기관을 가깝게 연결하기 위해서 여러 단백질들이 상호작용을 하고 있다. 그 중에서도 글루코스-관련 단백질 75(Glucose-related protein 75; Grp75)는 다른 접촉막 단백질과는 다르게 칼슘 채널 단백질들을 중간에서 상호작용하며 연결시키기 때문에 기능적인 측면에서 중요할 것으로 생각된다. Grp75는 미토콘드리아의 칼슘 채널 중 하나인 Vdac1 (Voltage-dependent anion channel 1)과 소포체의 칼슘 채널 중 하나인 Ip3r1 (Inositol 1,4,5-trisphosphate receptor type 1)과 상호작용하면서 연결시켜 주고 있다. Grp75는 두 채널을 연결 시키면서 칼슘 이온의 흐름을 조절한다. 하지만, 두 채널 사이에서 조절을 했을 때 어떠한 현상을 나타내는지는 아직 밝혀지지 않았다.
신경 세포, 특히 중추 신경계의 손상은 재생이 잘 되지 않는다. 신경 손상 치료를 위해서는 재생하는 신경 세포의 기작을 이해할 필요가 있다. 최근 연구들에서 재생 중인 신경세포에서의 소포체와 미토콘드리아 각각의 역할들이 밝혀지고 있다. 신경 재생을 위해서는 세포막의 재생성, 세포 골격의 재구성 등을 위해서 국지적으로 높은 에너지를 요구한다. 미토콘드리아의 이동 및 재배치는 국지적인 에너지 생성에 중요한 것이 밝혀졌다. 재생하는 신경 세포에서 소포체는 세포막 재생성, 세포 신호 전달에 필요한 칼슘 이온 농도를 조절하는 데에 관여한다. 미토콘드리아 뿐만 아니라 소포체도 손상을 입은 축색 돌기의 끝에 재배치 됨으로써 국지적으로 신경 재생을 조절한다.
미토콘드리아와 소포체 접촉막의 중요성은 강조되고 있고, 신경 재생에서의 미토콘드리아와 소포체 각각의 역할은 규명이 되고 있지만, 접촉막을 통한 신경 재생에서의 역할은 아직 밝혀지지 않았다. Grp75의 mRNA가 손상된 신경 세포 축색 돌기의 끝으로 이동된다는 연구 결과가 있지만, 신경 재생과 Grp75의 관련성에 대한 연구는 미비한 실정이다.
본 발명의 목적은 글루코스-관련 단백질 75(Glucose-related protein 75; Grp75) 단백질, Grp75 단백질 발현 촉진제 또는 활성화제를 유효성분으로 포함하는 신경 손상 질환 예방, 개선 또는 치료용 조성물과, Grp75 단백질 발현 수준 측정을 통한 신경 손상 질환 치료제 스크리닝 방법을 제공하는데 있다.
본 발명은 글루코스-관련 단백질 75(Glucose-related protein 75; Grp75) 단백질, Grp75 단백질 발현 촉진제 또는 활성화제를 유효성분으로 포함하는 신경 손상 질환 예방 또는 치료용 약학조성물을 제공한다.
또한, 본 발명은 Grp75 단백질, Grp75 단백질 발현 촉진제 또는 활성화제를 유효성분으로 포함하는 신경 손상 질환 예방 또는 개선용 건강식품 조성물을 제공한다.
또한, 본 발명은 (1) 신경세포에 시험물질을 접촉시키는 단계; (2) 상기 시험물질을 접촉한 신경세포에서 Grp75 단백질의 발현 또는 활성 정도를 측정하는 단계; 및 (3) 대조구 시료와 비교하여 상기 Grp75 단백질의 발현 또는 활성 정도가 증가한 시험물질을 선별하는 단계를 포함하는 신경 손상 질환 치료제 스크리닝 방법을 제공한다.
본 발명은 글루코스-관련 단백질 75(Glucose-related protein 75; Grp75) 단백질을 유효성분으로 포함하는 신경 손상 질환 예방 또는 치료용 조성물에 관한 것으로서, Grp75 단백질의 과발현이 소포체로부터의 미토콘드리아로의 칼슘 이동을 활성화 시켜, 신경재생에 기본적으로 필요한 에너지를 더 생성하게 만드는 것을 확인하였으며, 세포 배양에서 Grp75 단백질 과발현이 신경 재생을 촉진하는 것을 확인하였다. 이에, Grp75 단백질은 중추 신경 및 말초 신경 손상 치료제 개발에 유용하게 활용될 수 있을 것으로 기대된다.
도 1은 Grp75 과발현 시 세포질과 미토콘드리아의 칼슘이온과 ATP 변화를 나타낸다. (A) Grp75를 과발현시킨 신경세포의 축색 돌기를 절단한 후, 세포질 칼슘 지표(GEM-GECO)를 이용해 축색 돌기 끝 부분의 칼슘 이온 변화를 측정한 이미지. Ctrl pcDNA: 대조군. cytGrp75: Grp75 과발현 실험군. 스케일바는 10um. (B) 도 1A를 정량해 수치화시킨 그래프. 대조군과 실험군 각각 8, 7개의 세포에서 측정하고, 오차막대는 SEM으로 계산되었다. (C) 미토콘드리아 칼슘 지표(mito-case12)를 이용해 칼슘 이온 변화를 도 1B와 같은 방법으로 정량화한 그래프. 대조군과 실험군 각각 7, 10개의 세포에서 측정하고 오차 막대는 SEM으로 계산되었다. (D) 도 1A와 같은 방법으로, 세포질 ATP 지표 (AT1.03)을 이용해 축색 돌기 끝 부분의 칼슘 이온 변화를 측정한 이미지. (E) 도 1D를 정량화한 그래프. 각각 5, 7개의 세포에서 측정하고, 오차막대는 SEM으로 계산되었다. (F) 미토콘드리아 ATP 지표(mito-AT1.03)를 이용해 ATP 변화를 도 1E와 같은 방법으로 정량화한 그래프. 각각 7개의 세포에서 측정하고, 오차막대는 SEM으로 계산되었다.
도 2는 Grp75 과발현 시 마우스(mouse) 해마 신경(primary hippocampal neuron) 세포 재생 결과를 나타낸다. (A) 해마 신경 세포를 배양 4일 후 축색 돌기 부분을 절단한 후 3일 뒤 Tau1 (축색 돌기 표지)로 염색해 신경 세포 재생 정도를 확인하였다. Grp75: full-length Grp75 (전체 길이의 Grp75 단백질), cytGrp75: cytosolic Grp75 (미토콘드리아 표적 시퀀스를 없애 오로지 세포질에서 소포체와 미토콘드리아 사이에 연결 단백질로만 역할), MTS-cytGrp75: Cox8a mitochondrial targeting sequence added cytosolic Grp75 (미토콘드리아 단백질인 Cox8a의 미토콘드리아 표적 시퀀스를 달아 미토콘드리아 기질로 모두 들어가 연결 역할을 하지 못함). 스케일바는 200um. (B) 그림 2-A의 축색돌기의 길이를 재어 나타낸 그래프임. n=294-943개의 축색돌기, 4-7번 동일한 실험을 반복하였다. ** p<0.0001.
도 3은 Grp75가 연결하는 Ip3r1을 활성 혹은 비활성 시키는 화학물질을 처리하였을 때의 신경 재생 결과를 나타낸다. (A) 마우스의 해마 신경 세포를 배양 후 4일 뒤에 축색 돌기를 절단하면서 화학물질을 처리하였다. 3일 동안 재생시킨 후 축색 돌기 표지인 GAP43로 염색한 이미지. No treat: 아무것도 처리하지 않은 대조군, Xes C: Xestospongin C(Ip3r1의 비활성 물질), AdA: Adenophostin A(Ip3r의 활성화 물질). 스케일바는 200um. (B) 도 3A에서 축색 돌기의 길이를 재어 나타낸 그래프. N= 484-990개의 축색돌기, 7-8번의 동일한 실험을 반복하였다. *p<0.01, **p<0.0001.
도 4는 Grp75 과발현 시 쥐의 좌골 신경에서의 신경 재생 결과를 나타낸다. 척수에 렌티바이러스를 주사함으로써 Grp75를 과발현시킨 후, 좌골 신경에 손상을 준 뒤 3일 후, GAP43 (신경 세포 재생 마커)를 염색하여, 신경 재생 정도를 확인하였다. 스케일바는 2mm.
도 2는 Grp75 과발현 시 마우스(mouse) 해마 신경(primary hippocampal neuron) 세포 재생 결과를 나타낸다. (A) 해마 신경 세포를 배양 4일 후 축색 돌기 부분을 절단한 후 3일 뒤 Tau1 (축색 돌기 표지)로 염색해 신경 세포 재생 정도를 확인하였다. Grp75: full-length Grp75 (전체 길이의 Grp75 단백질), cytGrp75: cytosolic Grp75 (미토콘드리아 표적 시퀀스를 없애 오로지 세포질에서 소포체와 미토콘드리아 사이에 연결 단백질로만 역할), MTS-cytGrp75: Cox8a mitochondrial targeting sequence added cytosolic Grp75 (미토콘드리아 단백질인 Cox8a의 미토콘드리아 표적 시퀀스를 달아 미토콘드리아 기질로 모두 들어가 연결 역할을 하지 못함). 스케일바는 200um. (B) 그림 2-A의 축색돌기의 길이를 재어 나타낸 그래프임. n=294-943개의 축색돌기, 4-7번 동일한 실험을 반복하였다. ** p<0.0001.
도 3은 Grp75가 연결하는 Ip3r1을 활성 혹은 비활성 시키는 화학물질을 처리하였을 때의 신경 재생 결과를 나타낸다. (A) 마우스의 해마 신경 세포를 배양 후 4일 뒤에 축색 돌기를 절단하면서 화학물질을 처리하였다. 3일 동안 재생시킨 후 축색 돌기 표지인 GAP43로 염색한 이미지. No treat: 아무것도 처리하지 않은 대조군, Xes C: Xestospongin C(Ip3r1의 비활성 물질), AdA: Adenophostin A(Ip3r의 활성화 물질). 스케일바는 200um. (B) 도 3A에서 축색 돌기의 길이를 재어 나타낸 그래프. N= 484-990개의 축색돌기, 7-8번의 동일한 실험을 반복하였다. *p<0.01, **p<0.0001.
도 4는 Grp75 과발현 시 쥐의 좌골 신경에서의 신경 재생 결과를 나타낸다. 척수에 렌티바이러스를 주사함으로써 Grp75를 과발현시킨 후, 좌골 신경에 손상을 준 뒤 3일 후, GAP43 (신경 세포 재생 마커)를 염색하여, 신경 재생 정도를 확인하였다. 스케일바는 2mm.
본 발명은 글루코스-관련 단백질 75(Glucose-related protein 75; Grp75) 단백질, Grp75 단백질 발현 촉진제 또는 활성화제를 유효성분으로 포함하는 신경 손상 질환 예방 또는 치료용 약학조성물을 제공한다.
상세하게는, 상기 Grp75 단백질은 서열번호 1로 표시되는 Grp75 전장 단백질 또는 서열번호 2로 표시되는 Grp75 단백질 단편일 수 있으며, 상기 서열번호 2로 표시되는 Grp75 단백질 단편은 Grp75 전장 단백질에서 미토콘드리아 표적 서열을 제거한 세포질 표적 Grp75 단백질 단편일 수 있으나, 이에 한정되는 것은 아니다.
상세하게는, 상기 Grp75 단백질 발현 촉진제 또는 활성화제는 Grp75 단백질에 특이적으로 결합하는 화합물, 펩타이드, 앱타머 및 항체로 이루어진 군에서 선택될 수 있으나, 이에 한정되는 것은 아니다. 보다 상세하게는, 상기 Grp75 단백질 발현 촉진제 또는 활성화제는 아데노포스틴 A(Adenophostin A; AdA)일 수 있으나, 이에 한정되는 것은 아니다.
상세하게는, 상기 약학조성물은 소포체로부터 미토콘드리아로의 칼슘 이동을 활성화시켜, ATP 생성을 증가시킬 수 있으나, 이에 한정되는 것은 아니다.
상세하게는, 상기 약학조성물은 중추 신경 또는 말초 신경의 재생을 촉진할 수 있으나, 이에 한정되는 것은 아니다.
상세하게는, 상기 신경 손상 질환은 운동뉴런질환, 신경근질환, 신경총질환, 흉곽출구압박증후군, 말초신경장해, 신경선유종증, 신경근전달 질환, 허혈성 뇌질환, 뇌졸증(stroke), 뇌전증(epilepsy), 중풍 및 근위축성측색경화증(amyotrophic lateral sclerosis), 다발성경화증(Multiple sclerosis) 및 탈수초질환(demyelinating disease)일 수 있으나, 이에 한정되는 것은 아니다.
본 발명의 약학 조성물은 화학물질, 뉴클레오타이드, 안티센스, siRNA 올리고뉴클레오타이드 및 천연물 추출물을 유효성분으로 포함할 수 있다. 본 발명의 약학 조성물 또는 복합 제제는 유효 성분 이외에 약제학적으로 적합하고 생리학적으로 허용되는 보조제를 사용하여 제조될 수 있으며, 상기 보조제로는 부형제, 붕해제, 감미제, 결합제, 피복제, 팽창제, 윤활제, 활택제 또는 향미제 등의 가용화제를 사용할 수 있다. 본 발명의 약학 조성물은 투여를 위해서 유효 성분 이외에 추가로 약제학적으로 허용 가능한 담체를 1 종 이상 포함하여 약학 조성물로 바람직하게 제제화할 수 있다. 액상 용액으로 제제화되는 조성물에 있어서 허용 가능한 약제학적 담체로는, 멸균 및 생체에 적합한 것으로서, 식염수, 멸균수, 링거액, 완충 식염수, 알부민 주사용액, 덱스트로즈 용액, 말토 덱스트린 용액, 글리세롤, 에탄올 및 이들 성분 중 1 성분 이상을 혼합하여 사용할 수 있으며, 필요에 따라 항산화제, 완충액, 정균제 등 다른 통상의 첨가제를 첨가할 수 있다. 또한 희석제, 분산제, 계면활성제, 결합제 및 윤활제를 부가적으로 첨가하여 수용액, 현탁액, 유탁액 등과 같은 주사용 제형, 환약, 캡슐, 과립 또는 정제로 제제화할 수 있다.
본 발명의 약학 조성물의 약제 제제 형태는 과립제, 산제, 피복정, 정제, 캡슐제, 좌제, 시럽, 즙, 현탁제, 유제, 점적제 또는 주사 가능한 액제 및 활성 화합물의 서방출형 제제 등이 될 수 있다. 본 발명의 약학 조성물은 정맥내, 동맥내, 복강내, 근육내, 동맥내, 복강내, 흉골내, 경피, 비측내, 흡입, 국소, 직장, 경구, 안구내 또는 피내 경로를 통해 통상적인 방식으로 투여할 수 있다. 본 발명의 약학 조성물의 유효성분의 유효량은 질환의 예방 또는 치료 요구되는 양을 의미한다. 따라서, 질환의 종류, 질환의 중증도, 조성물에 함유된 유효 성분 및 다른 성분의 종류 및 함량, 제형의 종류 및 환자의 연령, 체중, 일반 건강 상태, 성별 및 식이, 투여 시간, 투여 경로 및 조성물의 분비율, 치료 기간, 동시 사용되는 약물을 비롯한 다양한 인자에 따라 조절될 수 있다. 이에 제한되는 것은 아니나, 예컨대, 성인의 경우, 1일 1회 내지 수회 투여시, 본 발명의 조성물은 1일 1회 내지 수회 투여시, 화합물일 경우 0.1ng/kg~10g/kg, 폴리펩타이드, 단백질 또는 항체일 경우 0.1ng/kg~10g/kg, 안티센스 뉴클레오타이드, siRNA, shRNAi, miRNA일 경우 0.01ng/kg~10g/kg의 용량으로 투여할 수 있다.
또한, 본 발명은 Grp75 단백질, Grp75 단백질 발현 촉진제 또는 활성화제를 유효성분으로 포함하는 신경 손상 질환 예방 또는 개선용 건강식품 조성물을 제공한다.
상세하게는, 상기 Grp75 단백질은 서열번호 1로 표시되는 Grp75 전장 단백질 또는 서열번호 2로 표시되는 Grp75 단백질 단편일 수 있으며, 상기 서열번호 2로 표시되는 Grp75 단백질 단편은 Grp75 전장 단백질에서 미토콘드리아 표적 서열을 제거한 세포질 표적 Grp75 단백질 단편일 수 있으나, 이에 한정되는 것은 아니다.
본 발명의 건강식품 조성물은 분말, 과립, 정제, 캡슐, 시럽, 음료 또는 환의 형태로 제공될 수 있으며, 상기 건강식품 조성물은 본 발명의 유효성분 이외에 다른 식품 또는 식품 첨가물과 함께 사용되고, 통상적인 방법에 따라 적절하게 사용될 수 있다. 유효성분의 혼합양은 그의 사용 목적 예를 들어 예방, 건강 또는 치료적 처치에 따라 적합하게 결정될 수 있다.
상기 건강식품 조성물에 함유된 유효용량은 상기 약학조성물의 유효용량에 준해서 사용할 수 있으나, 건강 및 위생을 목적으로 하거나 또는 건강 조절을 목적으로 하는 장기간의 섭취의 경우에는 상기 범위 이하일 수 있으며, 유효성분은 안전성 면에서 아무런 문제가 없기 때문에 상기 범위 이상의 양으로도 사용될 수 있음은 확실하다.
상기 건강식품의 종류에는 특별한 제한이 없고, 예로는 육류, 소세지, 빵, 쵸코렛, 캔디류, 스넥류, 과자류, 피자, 라면, 기타 면류, 껌류, 아이스크림류를 포함한 낙농제품, 각종 스프, 음료수, 차, 드링크제, 알콜 음료 및 비타민 복합제 등을 들 수 있다.
본 발명은 (1) 신경세포에 시험물질을 접촉시키는 단계; (2) 상기 시험물질을 접촉한 신경세포에서 Grp75 단백질의 발현 또는 활성 정도를 측정하는 단계; 및 (3) 대조구 시료와 비교하여 상기 Grp75 단백질의 발현 또는 활성 정도가 증가한 시험물질을 선별하는 단계를 포함하는 신경 손상 질환 치료제 스크리닝 방법을 제공한다.
상세하게는, 상기 Grp75 단백질은 서열번호 1로 표시되는 Grp75 전장 단백질 또는 서열번호 2로 표시되는 Grp75 단백질 단편일 수 있으며, 상기 서열번호 2로 표시되는 Grp75 단백질 단편은 Grp75 전장 단백질에서 미토콘드리아 표적 서열을 제거한 세포질 표적 Grp75 단백질 단편일 수 있으나, 이에 한정되는 것은 아니다.
상세하게는, 상기 신경 손상 질환은 운동뉴런질환, 신경근질환, 신경총질환, 흉곽출구압박증후군, 말초신경장해, 신경선유종증, 신경근전달 질환, 허혈성 뇌질환, 뇌졸증(stroke), 뇌전증(epilepsy), 중풍 및 근위축성측색경화증(amyotrophic lateral sclerosis), 다발성경화증(Multiple sclerosis) 및 탈수초질환(demyelinating disease)일 수 있으나, 이에 한정되는 것은 아니다.
본 발명의 스크리닝 방법을 언급하면서 사용되는 용어 "시험물질"은 유전자의 발현량에 영향을 미치거나, 단백질의 발현 또는 활성에 영향을 미치는지 여부를 검사하기 위하여 스크리닝에서 이용되는 미지의 후보 물질을 의미한다. 상기 시료는 화학물질, 뉴클레오타이드, 안티센스-RNA, siRNA(small interference RNA) 및 천연물 추출물을 포함하나, 이에 제한되는 것은 아니다.
이하, 본 발명의 이해를 돕기 위하여 실시예를 들어 상세하게 설명하기로 한다. 다만 하기의 실시예는 본 발명의 내용을 예시하는 것일 뿐 본 발명의 범위가 하기 실시예에 한정되는 것은 아니다. 본 발명의 실시예는 당업계에서 평균적인 지식을 가진 자에게 본 발명을 보다 완전하게 설명하기 위해 제공되는 것이다.
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1>
Grp75
과발현 시 세포질과 미토콘드리아의 칼슘이온과 ATP 변화 확인
본 발명자들은 Grp75 단백질을 과발현시켜 소포체와 미토콘드리아의 막접촉을 증가시킴으로써, 세포 본래의 기능을 향상시켜서 손상된 신경을 재생시키는 것을 확인하고자 했다. 첫번째로, Grp75가 칼슘채널을 통해 소포체와 미토콘드리아의 접촉을 하고 있다는 사실에 근거, 그리고 미토콘드리아 기질의 칼슘 이온이 세포의 에너지인 ATP 생성에 관여한다는 것에 근거하여, Grp75 단백질의 과발현이 소포체로부터의 미토콘드리아로의 칼슘 이동을 활성화 시켜, 신경재생에 기본적으로 필요한 에너지를 더욱 더 생성하게 만드는 것을 확인했다(도 1). 즉, Grp75 단백질의 과발현은 에너지 생성이라는 세포의 기능을 증가시키는 것을 보여주었다.
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2> 세포 배양에서
Grp75
단백질 과발현시 신경 재생 촉진 확인
세포 배양에서 Grp75 단백질 과발현이 신경 재생을 촉진하는지를 확인하였다. Grp75 단백질은 미토콘드리아 표적 서열이 존재하기 때문에, 미토콘드리아의 기질에 주로 분포하고 일부가 세포질에 존재하며 소포체와 미토콘드리아의 접촉막에 존재한다. 본 발명자들은 세포질에 존재하는 Grp75 만이 접촉막의 기능을 향상시킴으로써 신경재생을 촉진시킬 것으로 예상했기 때문에, 미토콘드리아 표적 서열(아미노산 서열 2-51)을 제거한 세포질 표적 Grp75(cytGrp75)의 과발현이 신경 세포 재생에 미치는 영향을 마우스의 해마 신경 세포를 배양한 것을 통해 확인하였다. 오직 세포질 표적 Grp75 만이 신경 세포 재생을 촉진했고, 미토콘드리아 기질에 존재하는 Grp75는 영향을 주지 않았다(도 2). 즉, 상기 결과는 Grp75 단백질의 신경 손상 치료제로써의 가능성을 보여주었다.
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3> 소포체로부터의 칼슘 전달이 신경 재생에 영향을 주는지 확인
소포체로부터의 칼슘 전달이 신경 재생에 영향을 주는지를 확인하였다. Grp75 단백질은 Ip3r1 단백질과 상호작용하고 칼슘전달에 영향을 주기 때문에, 본 발명자들은 Ip3r1 특이적인 활성과 비활성을 시키는 화학물질을 신경 세포가 손상입었을 때 처리함으로써, 어떠한 영향을 주는지를 확인하였다. Ip3r1을 활성화 시켰을 때 신경 재생이 촉진되는 것을 확인했다(도 3).
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4>
Grp75
단백질을 통한 신경 재생 촉진을 생체 내에서 확인
Grp75 단백질을 통한 신경 재생 촉진을 생체 내에서 확인하기 위해, 실험용 마우스에 렌티바이러스를 이용하여 Grp75 단백질을 과발현시켰다. 좌골신경에 압력을 가해 손상을 준 뒤, 재생하는 신경 세포 마커인 GAP43 단백질 항체로 염색을 하여 재생된 정도를 확인했다. 그 결과, Grp75 단백질을 과발현 시킨 쥐의 좌골신경의 재생이 촉진된 것을 확인하였다(도 4). 이러한 결과들은 Grp75 단백질이 신경 손상 치료제로서의 가능성을 보여주고 있다.
즉, 본 발명자들은 Grp75 단백질을 이용한 신경 손상 치료제의 개발을 목표로 하고 있고, 위의 실험 결과에서 볼 수 있듯이 Grp75 단백질의 과발현을 통해 본래 존재하고 있던 세포의 기능을 향상시켜 신경 재생을 촉진할 수 있다고 생각된다. 또한, 도 2는 해마 신경세포를 이용, 도 3은 좌골신경을 이용했다는 점에서, 중추 신경 및 말초 신경 손상 두 가지 모두의 치료제로써 사용 가능할 것으로 생각된다.
<110> ULSAN NATIONAL INSTITUTE OF SCIENCE AND TECHNOLOGY
<120> Composition for preventing or treating neuronal damage comprising
Grp75 protein
<130> ADP-2018-0231
<160> 2
<170> KopatentIn 2.0
<210> 1
<211> 679
<212> PRT
<213> Mus musculus
<400> 1
Met Ile Ser Ala Ser Arg Ala Ala Ala Ala Arg Leu Val Gly Thr Ala
1 5 10 15
Ala Ser Arg Ser Pro Ala Ala Ala Arg Pro Gln Asp Gly Trp Asn Gly
20 25 30
Leu Ser His Glu Ala Phe Arg Phe Val Ser Arg Arg Asp Tyr Ala Ser
35 40 45
Glu Ala Ile Lys Gly Ala Val Val Gly Ile Asp Leu Gly Thr Thr Asn
50 55 60
Ser Cys Val Ala Val Met Glu Gly Lys Gln Ala Lys Val Leu Glu Asn
65 70 75 80
Ala Glu Gly Ala Arg Thr Thr Pro Ser Val Val Ala Phe Thr Ala Asp
85 90 95
Gly Glu Arg Leu Val Gly Met Pro Ala Lys Arg Gln Ala Val Thr Asn
100 105 110
Pro Asn Asn Thr Phe Tyr Ala Thr Lys Arg Leu Ile Gly Arg Arg Tyr
115 120 125
Asp Asp Pro Glu Val Gln Lys Asp Thr Lys Asn Val Pro Phe Lys Ile
130 135 140
Val Arg Ala Ser Asn Gly Asp Ala Trp Val Glu Ala His Gly Lys Leu
145 150 155 160
Tyr Ser Pro Ser Gln Ile Gly Ala Phe Val Leu Met Lys Met Lys Glu
165 170 175
Thr Ala Glu Asn Tyr Leu Gly His Thr Ala Lys Asn Ala Val Ile Thr
180 185 190
Val Pro Ala Tyr Phe Asn Asp Ser Gln Arg Gln Ala Thr Lys Asp Ala
195 200 205
Gly Gln Ile Ser Gly Leu Asn Val Leu Arg Val Ile Asn Glu Pro Thr
210 215 220
Ala Ala Ala Leu Ala Tyr Gly Leu Asp Lys Ser Glu Asp Lys Val Ile
225 230 235 240
Ala Val Tyr Asp Leu Gly Gly Gly Thr Phe Asp Ile Ser Ile Leu Glu
245 250 255
Ile Gln Lys Gly Val Phe Glu Val Lys Ser Thr Asn Gly Asp Thr Phe
260 265 270
Leu Gly Gly Glu Asp Phe Asp Gln Ala Leu Leu Arg His Ile Val Lys
275 280 285
Glu Phe Lys Arg Glu Thr Gly Val Asp Leu Thr Lys Asp Asn Met Ala
290 295 300
Leu Gln Arg Val Arg Glu Ala Ala Glu Lys Ala Lys Cys Glu Leu Ser
305 310 315 320
Ser Ser Val Gln Thr Asp Ile Asn Leu Pro Tyr Leu Thr Met Asp Ala
325 330 335
Ser Gly Pro Lys His Leu Asn Met Lys Leu Thr Arg Ala Gln Phe Glu
340 345 350
Gly Ile Val Thr Asp Leu Ile Lys Arg Thr Ile Ala Pro Cys Gln Lys
355 360 365
Ala Met Gln Asp Ala Glu Val Ser Lys Ser Asp Ile Gly Glu Val Ile
370 375 380
Leu Val Gly Gly Met Thr Arg Met Pro Lys Val Gln Gln Thr Val Gln
385 390 395 400
Asp Leu Phe Gly Arg Ala Pro Ser Lys Ala Val Asn Pro Asp Glu Ala
405 410 415
Val Ala Ile Gly Ala Ala Ile Gln Gly Gly Val Leu Ala Gly Asp Val
420 425 430
Thr Asp Val Leu Leu Leu Asp Val Thr Pro Leu Ser Leu Gly Ile Glu
435 440 445
Thr Leu Gly Gly Val Phe Thr Lys Leu Ile Asn Arg Asn Thr Thr Ile
450 455 460
Pro Thr Lys Lys Ser Gln Val Phe Ser Thr Ala Ala Asp Gly Gln Thr
465 470 475 480
Gln Val Glu Ile Lys Val Cys Gln Gly Glu Arg Glu Met Ala Gly Asp
485 490 495
Asn Lys Leu Leu Gly Gln Phe Thr Leu Ile Gly Ile Pro Pro Ala Pro
500 505 510
Arg Gly Val Pro Gln Ile Glu Val Thr Phe Asp Ile Asp Ala Asn Gly
515 520 525
Ile Val His Val Ser Ala Lys Asp Lys Gly Thr Gly Arg Glu Gln Gln
530 535 540
Ile Val Ile Gln Ser Ser Gly Gly Leu Ser Lys Asp Asp Ile Glu Asn
545 550 555 560
Met Val Lys Asn Ala Glu Lys Tyr Ala Glu Glu Asp Arg Arg Lys Lys
565 570 575
Glu Arg Val Glu Ala Val Asn Met Ala Glu Gly Ile Ile His Asp Thr
580 585 590
Glu Thr Lys Met Glu Glu Phe Lys Asp Gln Leu Pro Ala Asp Glu Cys
595 600 605
Asn Lys Leu Lys Glu Glu Ile Ser Lys Met Arg Ala Leu Leu Ala Gly
610 615 620
Lys Asp Ser Glu Thr Gly Glu Asn Ile Arg Gln Ala Ala Ser Ser Leu
625 630 635 640
Gln Gln Ala Ser Leu Lys Leu Phe Glu Met Ala Tyr Lys Lys Met Ala
645 650 655
Ser Glu Arg Glu Gly Ser Gly Ser Ser Gly Thr Gly Glu Gln Lys Glu
660 665 670
Asp Gln Lys Glu Glu Lys Gln
675
<210> 2
<211> 629
<212> PRT
<213> Mus musculus
<400> 2
Met Lys Gly Ala Val Val Gly Ile Asp Leu Gly Thr Thr Asn Ser Cys
1 5 10 15
Val Ala Val Met Glu Gly Lys Gln Ala Lys Val Leu Glu Asn Ala Glu
20 25 30
Gly Ala Arg Thr Thr Pro Ser Val Val Ala Phe Thr Ala Asp Gly Glu
35 40 45
Arg Leu Val Gly Met Pro Ala Lys Arg Gln Ala Val Thr Asn Pro Asn
50 55 60
Asn Thr Phe Tyr Ala Thr Lys Arg Leu Ile Gly Arg Arg Tyr Asp Asp
65 70 75 80
Pro Glu Val Gln Lys Asp Thr Lys Asn Val Pro Phe Lys Ile Val Arg
85 90 95
Ala Ser Asn Gly Asp Ala Trp Val Glu Ala His Gly Lys Leu Tyr Ser
100 105 110
Pro Ser Gln Ile Gly Ala Phe Val Leu Met Lys Met Lys Glu Thr Ala
115 120 125
Glu Asn Tyr Leu Gly His Thr Ala Lys Asn Ala Val Ile Thr Val Pro
130 135 140
Ala Tyr Phe Asn Asp Ser Gln Arg Gln Ala Thr Lys Asp Ala Gly Gln
145 150 155 160
Ile Ser Gly Leu Asn Val Leu Arg Val Ile Asn Glu Pro Thr Ala Ala
165 170 175
Ala Leu Ala Tyr Gly Leu Asp Lys Ser Glu Asp Lys Val Ile Ala Val
180 185 190
Tyr Asp Leu Gly Gly Gly Thr Phe Asp Ile Ser Ile Leu Glu Ile Gln
195 200 205
Lys Gly Val Phe Glu Val Lys Ser Thr Asn Gly Asp Thr Phe Leu Gly
210 215 220
Gly Glu Asp Phe Asp Gln Ala Leu Leu Arg His Ile Val Lys Glu Phe
225 230 235 240
Lys Arg Glu Thr Gly Val Asp Leu Thr Lys Asp Asn Met Ala Leu Gln
245 250 255
Arg Val Arg Glu Ala Ala Glu Lys Ala Lys Cys Glu Leu Ser Ser Ser
260 265 270
Val Gln Thr Asp Ile Asn Leu Pro Tyr Leu Thr Met Asp Ala Ser Gly
275 280 285
Pro Lys His Leu Asn Met Lys Leu Thr Arg Ala Gln Phe Glu Gly Ile
290 295 300
Val Thr Asp Leu Ile Lys Arg Thr Ile Ala Pro Cys Gln Lys Ala Met
305 310 315 320
Gln Asp Ala Glu Val Ser Lys Ser Asp Ile Gly Glu Val Ile Leu Val
325 330 335
Gly Gly Met Thr Arg Met Pro Lys Val Gln Gln Thr Val Gln Asp Leu
340 345 350
Phe Gly Arg Ala Pro Ser Lys Ala Val Asn Pro Asp Glu Ala Val Ala
355 360 365
Ile Gly Ala Ala Ile Gln Gly Gly Val Leu Ala Gly Asp Val Thr Asp
370 375 380
Val Leu Leu Leu Asp Val Thr Pro Leu Ser Leu Gly Ile Glu Thr Leu
385 390 395 400
Gly Gly Val Phe Thr Lys Leu Ile Asn Arg Asn Thr Thr Ile Pro Thr
405 410 415
Lys Lys Ser Gln Val Phe Ser Thr Ala Ala Asp Gly Gln Thr Gln Val
420 425 430
Glu Ile Lys Val Cys Gln Gly Glu Arg Glu Met Ala Gly Asp Asn Lys
435 440 445
Leu Leu Gly Gln Phe Thr Leu Ile Gly Ile Pro Pro Ala Pro Arg Gly
450 455 460
Val Pro Gln Ile Glu Val Thr Phe Asp Ile Asp Ala Asn Gly Ile Val
465 470 475 480
His Val Ser Ala Lys Asp Lys Gly Thr Gly Arg Glu Gln Gln Ile Val
485 490 495
Ile Gln Ser Ser Gly Gly Leu Ser Lys Asp Asp Ile Glu Asn Met Val
500 505 510
Lys Asn Ala Glu Lys Tyr Ala Glu Glu Asp Arg Arg Lys Lys Glu Arg
515 520 525
Val Glu Ala Val Asn Met Ala Glu Gly Ile Ile His Asp Thr Glu Thr
530 535 540
Lys Met Glu Glu Phe Lys Asp Gln Leu Pro Ala Asp Glu Cys Asn Lys
545 550 555 560
Leu Lys Glu Glu Ile Ser Lys Met Arg Ala Leu Leu Ala Gly Lys Asp
565 570 575
Ser Glu Thr Gly Glu Asn Ile Arg Gln Ala Ala Ser Ser Leu Gln Gln
580 585 590
Ala Ser Leu Lys Leu Phe Glu Met Ala Tyr Lys Lys Met Ala Ser Glu
595 600 605
Arg Glu Gly Ser Gly Ser Ser Gly Thr Gly Glu Gln Lys Glu Asp Gln
610 615 620
Lys Glu Glu Lys Gln
625
Claims (13)
- 글루코스-관련 단백질 75(Glucose-related protein 75; Grp75) 단백질, Grp75 단백질 발현 촉진제 또는 활성화제를 유효성분으로 포함하는 신경 손상 질환 예방 또는 치료용 약학조성물.
- 제1항에 있어서, 상기 Grp75 단백질은 서열번호 1로 표시되는 Grp75 전장 단백질 또는 서열번호 2로 표시되는 Grp75 단백질 단편인 것을 특징으로 하는 신경 손상 질환 예방 또는 치료용 약학조성물.
- 제2항에 있어서, 상기 서열번호 2로 표시되는 Grp75 단백질 단편은 Grp75 전장 단백질에서 미토콘드리아 표적 서열을 제거한 세포질 표적 Grp75 단백질 단편인 것을 특징으로 하는 신경 손상 질환 예방 또는 치료용 약학조성물.
- 제1항에 있어서, 상기 Grp75 단백질 발현 촉진제 또는 활성화제는 Grp75 단백질에 특이적으로 결합하는 화합물, 펩타이드, 앱타머 및 항체로 이루어진 군에서 선택된 어느 하나인 것을 특징으로 하는 신경 손상 질환 예방 또는 치료용 약학조성물.
- 제4항에 있어서, 상기 Grp75 단백질 발현 촉진제 또는 활성화제는 아데노포스틴 A(Adenophostin A; AdA)인 것을 특징으로 하는 신경 손상 질환 예방 또는 치료용 약학조성물.
- 제1항에 있어서, 상기 약학조성물은 소포체로부터 미토콘드리아로의 칼슘 이동을 활성화시켜, ATP 생성을 증가시키는 것을 특징으로 하는 신경 손상 질환 예방 또는 치료용 약학조성물.
- 제1항에 있어서, 상기 약학조성물은 중추 신경 또는 말초 신경의 재생을 촉진하는 것을 특징으로 하는 신경 손상 질환 예방 또는 치료용 약학조성물.
- 제1항 내지 제7항 중 어느 한 항에 있어서, 상기 신경 손상 질환은 운동뉴런질환, 신경근질환, 신경총질환, 흉곽출구압박증후군, 말초신경장해, 신경선유종증, 신경근전달 질환, 허혈성 뇌질환, 뇌졸증(stroke), 뇌전증(epilepsy), 중풍 및 근위축성측색경화증(amyotrophic lateral sclerosis), 다발성경화증(Multiple sclerosis) 및 탈수초질환(demyelinating disease)인 것을 특징으로 하는 신경 손상 질환 예방 또는 치료용 약학조성물.
- Grp75 단백질, Grp75 단백질 발현 촉진제 또는 활성화제를 유효성분으로 포함하는 신경 손상 질환 예방 또는 개선용 건강식품 조성물.
- 제9항에 있어서, 상기 Grp75 단백질은 서열번호 1로 표시되는 Grp75 전장 단백질 또는 서열번호 2로 표시되는 Grp75 단백질 단편인 것을 특징으로 하는 신경 손상 질환 예방 또는 개선용 건강식품 조성물.
- (1) 신경세포에 시험물질을 접촉시키는 단계;
(2) 상기 시험물질을 접촉한 신경세포에서 Grp75 단백질의 발현 또는 활성 정도를 측정하는 단계; 및
(3) 대조구 시료와 비교하여 상기 Grp75 단백질의 발현 또는 활성 정도가 증가한 시험물질을 선별하는 단계를 포함하는 신경 손상 질환 치료제 스크리닝 방법. - 제11항에 있어서, 상기 Grp75 단백질은 서열번호 1로 표시되는 Grp75 전장 단백질 또는 서열번호 2로 표시되는 Grp75 단백질 단편인 것을 특징으로 하는 신경 손상 질환 치료제 스크리닝 방법.
- 제11항에 있어서, 상기 신경 손상 질환은 운동뉴런질환, 신경근질환, 신경총질환, 흉곽출구압박증후군, 말초신경장해, 신경선유종증, 신경근전달 질환, 허혈성 뇌질환, 뇌졸증(stroke), 뇌전증(epilepsy), 중풍 및 근위축성측색경화증(amyotrophic lateral sclerosis), 다발성경화증(Multiple sclerosis) 및 탈수초질환 (demyelinating disease)인 것을 특징으로 하는 신경 손상 질환 치료제 스크리닝 방법.
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