SREBP를 조절하는 대사질환 신약후보물질 발굴 및 작용 기작 규명

다국어 초록 (Multilingual Abstract)

Purpose&Contents
- Elucidation of mechanisms by which SREBP regulates fat and glucose metabolism for preventing human metabolic diseases - Development of highly efficient chemical genetic systems that combine C. elegans and mammalian systems for the identification of anti-metabolic syndrome drug candidates
- Validation of mouse systems that test the efficacy of the candidate anti-metabolic syndeome chemicals
1. To establish C. elegans systems that can be used for studying the metabolism-regulatory roles of SREBP and the model of metabolic diseases
2. To identify and characterize candidate genetic factors that regulate SREBP
3. To elucidate mechanisms by which SREBP-regulatory genes modulate fat and carbohydrate metabolism
4. To screen potential factors that prevent metabolic diseases using SREBP reporters
5. To validate the efficacy of anti-metabolic syndrome chemicals that affect the expression of candidate genetic factors that regulate SREBP using cell culture systems
6. To evaluate the roles of anti-metabolic syndrome chemicals in mouse model systems
Results
Publication : SREBP and MDT-15 protect C. elegans from glucose-induced accelerated aging by preventing accumulation of saturated fat, 2015, Genes & Development Inhibition of elongin C promotes longevity and protein homeostasis via HIF-1 in C. elegans, 2015, AGING CELL RNA helicase SACY-1 is required for longevity caused by various genetic perturbations in Caenorhabditis elegans. 2016, Cell Cycle Inverse correlation between longevity and developmental rate among wild C. elegans strains, 2016, Aging Survival assays using Caenorhabditis elegans, 2017, MOLECULES AND CELLS RNA surveillance via nonsense-mediated mRNA decay is crucial for longevity in daf-2/insulin/IGF-1 mutant C. elegans, 2017, NATURE COMMUNICATIONS Longevity regulation by NMD-mediated mRNA quality control, 2017, BMB REPORTS The role of dietary carbohydrates in organismal aging, 2017, Cellular and Molecular Life Sciences
Conference presentations : “SREBP/MDT-15 transcription factor complex moderates toxic effects of glucose on lifespan by reducing saturated fat in C. elegans”, 2016, KSMCB winter conference, Yongpyeong, Korea “SREBP/SBP-1 and MDT-15 moderate the life-shortening effect of glucose by reducing saturated fatty acids”, 2016 Asia-Pacific Worm Meeting, Beijing, China “Distinct RNA helicases that promote longevity in Caenorhabditis elegans”, 2016 Asia-Pacific Worm Meeting, beijing, China “RNA helicases promote longevity via distinct functions in Caenorhabditis elegans”,28th KSMCB International Conference, Seoul, Korea “SREBP and MDT-15 protect C. elegans from toxic effects of glucose on lifespan by regulating lipid metabolism”,2016 IBS Conference: Genetics of Aging and Life History,Deagu,Korea “The role of Krebs cycle metabolites in innate immunity in C. elegans”, KSMCB Winter Conference 2016, Pyeongchang, Korea “Slow growing wild C. elegans strains tend to live long”,2016 KSG Spring conference, Deagu,Korea “Longevity inversely correlates with developmental rate among wild C. elegans strains”, 2016 Asia-Pacific Worm Meeting,beijing, China “The role of Krebs cycle enzymes in resistance against P. aeruginosa”,28th KSMCB International Conference,Seoul, Korea “Aging positively correlates with developmental rate among wild C. elegans strains”,28th KSMCB International Conference,Seoul, Korea “SREBP/MDT-15 Moderates Glucose-Induced Accelerated Aging by Reducing Saturated Fatty Acid levels in C. elegans”, 28th KSMCB International Conference,Seoul, Korea “C. elegans elongin C regulates longevity and proteostasis through hypoxia-inducible factor 1”,KSMCB Winter Conference 2016,Pyeongchang, Korea “Glutamine tRNA fragments promote longevity via increasing mitochondrial activity through AMP kinase in C. elegans”, 2016 Asia-Pacific Worm Meeting, beijing, China “longin C regulates longevity and protein homeostasis through hypoxia-inducible factor 1 in C. elegans”,Seoul, Korea “Identification of Genes that Mediate Glucose-Induced Accelerated Aging in C. elegans through RNAi Screens”, 2017 ICKSMCB , Seoul, Korea
Patents : “Methods for screening SREBP-regulating factors using transgenic Caenorhabditis elegans”, Seung-Jae V. Lee, Dongyeop Lee, 10-2016-0024163 “Caenorhabditis elegans that specifically displays suppressed developmental defects in an insulin/IGF-1 receptor mutant background”, Seung-Jae V. Lee, Wooseon Hwang, Ozlem Altintas, 10-2016-0025480 “Caenorhabditis elegans displaying anti-aging phenotype”, Hong Gil Nam, Gyoo Yeol Jung, Seung-Jae V. Lee, Wooseon Hwang, Gi Won Shin, Mihwa Seo, 10-2016-0049947
Ph.D. and M.S. : Ph.D.: Ara Hwang, Keunhee Seo, Mihwa Seo, Murat Artan, Dongyeop Lee, Dae-Eun Jeong, M.S.: Ozlem Altintas ,Juyoung Jung
Expected Contribution
- This proposal will provide better information regarding how SREBP regulates metabolism in vivo and will lead to better understanding of metabolic diseases
- This research will also identify useful drug candidates by using high-efficiency low-cost C. elegans systems
- The evaluation of the new drug candidates by using mouse and cell culture systems may have potential for treating metabolic syndrome

국문 초록 (Abstract)

연구의 목적 및 내용 : SREBP에 의한 생체 내 당 및 지질 대사 조절의 메커니즘을 밝혀 인간 대사 질환 억제 연구를 위한 기반을 구축함. 꼬마선충과 포유동물 시스템을 결합한 저비용 고효율의 화학 유전학적 대사 질환 연구 모델 시스템을 개발하여 신규 항대사질환 신약후보물질 및 그 타겟을 발굴함. 마우스를 이용하여 SREBP를 직간접적으로 타겟하는 항대사질환 신약후보물질의 효과를 확인함으로써 대사질환의 치료 기술 향상에 기여함. 본 연구는 비만, 대사증후군, 비알콜성지방간 등의 유전적 요인인 SREBP를 직간접적으로 타겟하는 신약후보물질을 발굴하고 그 작용 기작을 분석하기 위하여,
1. 꼬마선충에서 SREBP에 의한 대사 조절 기전 및 대사질환 모델 연구 기반을 구축함
2. SREBP를 조절하는 후보 유전자를 발굴하고 분석함
3. SREBP와 그 조절 유전자를 통한 당 및 지질 대사 조절의 기작을 규명함
4. SREBP 리포터를 이용하여 대사 질환 제어 신약후보물질을 스크린함
5. 신규 SREBP 조절 유전자 및 신약후보물질이 포유동물 세포 배양 시스템에서 대사에 미치는 영향을 분석함
6. 신규 SREBP 조절 유전자를 타겟하는 신약후보물질을 마우스 모델에서 검증 분석함
으로써 대사질환의 예방과 치료를 위한 획기적인 전략을 수립하고자 하는 중개 연구임.
연구개발성과
논문게재 : SREBP and MDT-15 protect C. elegans from glucose-induced accelerated aging by preventing accumulation of saturated fat, 2015, Genes & Development Inhibition of elongin C promotes longevity and protein homeostasis via HIF-1 in C. elegans, 2015, AGING CELL RNA helicase SACY-1 is required for longevity caused by various genetic perturbations in Caenorhabditis elegans. 2016, Cell Cycle Inverse correlation between longevity and developmental rate among wild C. elegans strains, 2016, Aging Survival assays using Caenorhabditis elegans, 2017, MOLECULES AND CELLS RNA surveillance via nonsense-mediated mRNA decay is crucial for longevity in daf-2/insulin/IGF-1 mutant C. elegans, 2017, NATURE COMMUNICATIONS Longevity regulation by NMD-mediated mRNA quality control, 2017, BMB REPORTS The role of dietary carbohydrates in organismal aging, 2017, Cellular and Molecular Life Sciences
학술발표 : 이동엽, “SREBP/MDT-15 transcription factor complex moderates toxic effects of glucose on lifespan by reducing saturated fat in C. elegans”, 2016년 한국분자세포생물학회 동계학술대회, 포스터발표, 한국, 용평 이동엽, “SREBP/SBP-1 and MDT-15 moderate the life-shortening effect of glucose by reducing saturated fatty acids”, 2016 Asia-Pacific Worm Meeting, 구두발표, 중국, 베이징 박상순, “Distinct RNA helicases that promote longevity in Caenorhabditis elegans”, 2016 Asia-Pacific Worm Meeting, 포스터발표(우수포스터상), 중국, 베이징 박상순, “RNA helicases promote longevity via distinct functions in Caenorhabditis elegans”,28th KSMCB International Conference,포스터발표,한국,서울 이동엽, “SREBP and MDT-15 protect C. elegans from toxic effects of glucose on lifespan by regulating lipid metabolism” ,2016 IBS Conference: Genetics of Aging and Life History, 포스터발표, 한국, 대구 이유진, “The role of Krebs cycle metabolites in innate immunity in C. elegans”, KSMCB Winter Conference 2016, 포스터발표, 한국, 평창 이유진,“Slow growing wild C. elegans strains tend to live long”,2016 한국노화학회 춘계학술대회, 포스터발표, 한국 ,대구 이유진,“Longevity inversely correlates with developmental rate among wild C. elegans strains”, 2016 Asia-Pacific Worm Meeting,포스터발표,중국,베이징 이유진,“The role of Krebs cycle enzymes in resistance against P. aeruginosa”,28th KSMCB International Conference,포스터발표,한국,서울 이유진,“Aging positively correlates with developmental rate among wild C. elegans strains”,28th KSMCB International Conference,포스터발표,한국,서울 정윤지,“SREBP/MDT-15 Moderates Glucose-Induced Accelerated Aging by Reducing Saturated Fatty Acid levels in C. elegans”, 28th KSMCB International Conference,포스터발표,한국,서울 황우선,“C. elegans elongin C regulates longevity and proteostasis through hypoxia-inducible factor 1”,KSMCB Winter Conference 2016,포스터발표,한국,평창 황우선,“Glutamine tRNA fragments promote longevity via increasing mitochondrial activity through AMP kinase in C. elegans”, 2016 Asia-Pacific Worm Meeting,포스터발표(우수포스터상), 중국, 베이징 황우선,“longin C regulates longevity and protein homeostasis through hypoxia-inducible factor 1 in C. elegans”,포스터발표,한국,서울 정윤지, “Identification of Genes that Mediate Glucose-Induced Accelerated Aging in C. elegans through RNAi Screens”, 2017 한국분자세포생물학회, 포스터발표, 한국, 서울
특허출원 : “형질전환 예쁜꼬마선충을 이용하여 SREBP 조절인자를 스크리닝하는 방법”, 이승재, 이동엽, 출원번호: 10-2016-0024163 “인슐린/IGF-1 수용체 결핍 돌연변이체의 발달결함만 특이적으로 억제된 예쁜꼬마선충”, 이승재, 황우선, Ozlem Altintas, 출원번호: 10-2016-0025480 “항노화 형질전환 예쁜꼬마선충”, 남홍길, 정규열, 이승재, 황우선, 신기원, 서미화, 출원번호: 10-2016-0049947
인력양성 : 박사: 황아라, 서근희, 서미화, Murat Artan, 이동엽, 정대은 석사: Ozlem Altintas, 정주영
연구개발성과의 활용계획(기대효과) : SREBP에 의한 대사 조절 기작을 규명함으로써 대사질환 이해를 위한 진일보된 관점 제공 꼬마선충의 저비용 고효율 시스템을 이용하여 중요 대사 조절 신규 유전자 및 케미컬을 스크린함으로써 신약후보물질 및 생체 내 타겟 발굴 가능 발굴된 신약후보물질을 포유동물세포 및 마우스로 검증하여 향후 임상연구 진입이 기대됨