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Kafe 바로가기주관연구기관 | 연세대학교 Yonsei University |
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연구책임자 | 김동욱 |
참여연구자 | 김종훈 , 김한수 , 이인석 |
보고서유형 | 최종보고서 |
발행국가 | 대한민국 |
언어 | 한국어 |
발행년월 | 2017-04 |
주관부처 | 미래창조과학부 Ministry of Science, ICT and Future Planning |
과제관리전문기관 | 한국연구재단 National Research Foundation of Korea |
등록번호 | TRKO202000007309 |
DB 구축일자 | 2020-09-26 |
키워드 | 전분화능 줄기세포.줄기세포 분화기술.조직재생.세포치료.시스템생물학.Human pluripotent stem cell.Differentiation.Tissue regeneration.Cell replacement therapy.Systems biology. |
○ 인간 전분화능 줄기세포로부터 중뇌 도파민 신경세포로의 분화기술에 대한 공정화/최적화를 완료하였음. 분화된 도파민 신경세포를 파킨슨병 소형 및 대형동물 모델에 이식하여 유효성과 안전성을 검증함. 분화 세포의 전사체를 정밀 분석하여 중뇌 도파민 전구세포를 선택적으로 분리 정제하는 표면마커를 발굴함. (논문/특허/기술이전 완료)
○ 간세포 분화기술을 개선하고 최적화하여 생산 수율 3배, 약물대사기능 2배 이상의 간세포 생산기법을 확립하였음. 분화 세포가 분비하는 단백질 중 간조직 재생촉진핵심인자로서 MFGE8 단백질을 발굴하고,
○ 인간 전분화능 줄기세포로부터 중뇌 도파민 신경세포로의 분화기술에 대한 공정화/최적화를 완료하였음. 분화된 도파민 신경세포를 파킨슨병 소형 및 대형동물 모델에 이식하여 유효성과 안전성을 검증함. 분화 세포의 전사체를 정밀 분석하여 중뇌 도파민 전구세포를 선택적으로 분리 정제하는 표면마커를 발굴함. (논문/특허/기술이전 완료)
○ 간세포 분화기술을 개선하고 최적화하여 생산 수율 3배, 약물대사기능 2배 이상의 간세포 생산기법을 확립하였음. 분화 세포가 분비하는 단백질 중 간조직 재생촉진핵심인자로서 MFGE8 단백질을 발굴하고, 동물모델을 이용하여 치료효과 검증에 성공함. (논문/특허/기술이전 완료)
○ 인간 전분화능 줄기세포 유래 신경전구세포와 중간엽줄기세포의 허혈성 뇌졸중에 대한 치료 효과 및 관련 분비단백체를 비교분석하고, 함유되어 있는 신경조직재생 촉진인자를 동정하여 치료기전을 규명함. (논문/특허/기술이전 완료)
○ 문헌정보를 분석하여 줄기세포 관련 인간 전사조절인자 네트워크 데이터베이스를 구축하고, 이를 활용하여 분화와 조직재생 관련 신규 전사조절인자 및 조직재생인자를 발굴함. (관련분야 상위 5% 권위지 게재 완료)
(출처 : 보고서 요약서 3p)
ㅇ Purpose & Contents
The goal of the proposed research is to develop in vitro differentiation protocols to derive highly functional neurons and hepatocytes from human pluripotent stem cell (hPSCs). For this purpose, this research will refine and optimize current protocols to improve cell-type sp
ㅇ Purpose & Contents
The goal of the proposed research is to develop in vitro differentiation protocols to derive highly functional neurons and hepatocytes from human pluripotent stem cell (hPSCs). For this purpose, this research will refine and optimize current protocols to improve cell-type specific functions and differentiation efficiency of the hPSC-derived cells up to clinically applicable levels using systems biology-based approaches. To elucidate the therapeutic mechanisms of hPSC-derived donor cells, this research will investigate therapeutic outcomes obtained not only by direct cell grafting, but also by delivering secreted proteome (secretome) from hPSC-derived neural and hepatic cells into injured tissues.
ㅇ Results
1. Development of the differentiation protocol for generating midbrain A9 region-specific dopaminergic neurons for Parkinson’s disease
a. Development of effective differentiation protocol for generating midbrain A9 region-specific dopaminergic neurons from human pluripotent stem cells and establishment of single cell dissociation and cryopreservation technique adequate to characters of each stage
b. Optimization of cell transplantation condition for animal models of Parkinson’s disease, verification of therapeutic efficacy/safety via behavioral/histological test and determination of differentiation stage suitable for cell transplantation in Parkinson’s animal model in terms of cellular function and survival
c. Characterization of A9 dopaminergic precursors and neurons differentiated from Lmx1a-EGFP and Pitx3-mCherry reporter cell line via microarray analysis and identification of 5 cell surface markers that can be used for isolation of A9 dopaminergic precursors
d. Securement of safe cell source via removing neural crest stem cells from heterogenous neural precursor populations and approach to commercial clinical study for spinal cord injury using these cells
2. Optimization of hepatic differentiation & Identification of anti-fibrotic protein in stem cell secretome
a. Optimization of the differentiation protocol for generating functional human hepatocytes that includes the step of amplifying the number of hepatic progenitors and the step of enhancing metabolic activities of drugs (Yield, >3; AVE metabolic acitivity, >2)
b. Identification of MFGE8 as a key therapeutic protein in the secretome and verification of the therapeutic effects of MFGE8 in animals with liver fibrosis
3. Proteomic studies on regenerating potential of secretome obtained from hPSC-derived neural progenitor cells and mesechymal stem cells
a. Studies on the therapeutic effect of hPSC-derived neural progenitors on the ischemic brain injury
b. Proteomic comparative analyses of secretomes obtained from hPSC-derived neural progenitors and mesenchymal stem cells
c. Investigation of the therapeutic molecular mechanism of secretome that promote the regeneration of neural tissues by collaboration with subprojects 1 and 4
4. Constructing a network related to stem cells and a research using this network.
a. Construction of the TRRUST network which is based on literature and construction of a human transcriptional regulation network using this network
b. Unraveling a function of secretome of mesenchymal cells using transcriptional regulation network
c. Finding membrane genes for differentiated hepatocyte using transcriptional regulation network
ㅇ Expected Contribution
● Through this study, generated A9 region-specific midbrain dopaminergic neurons can be contributed greatly to treat Parkinson’s disease. Moreover, cell surface markers of A9 dopaminergic precursors discovered in this study may lead to maximize cell therapy effect for Parkinson’s disease. in addition, our study will provide fundamental technologies in developing cell therapy products for neurological disorders including Parkinson’s disease and will benefit commercialization of differentiated cells through stepwise characterization of cells and our cryopreservation techniques.
● The patents involving the above achievements have been transferred to a company. Thus, together with the company, our team will develop and produce the commercial products of human stem cell-derived hepatocytes. In addition, regarding the MFGE8 protein, we’ll focus on the investigation on the mechanism of action and obtain data for the preclinical GLP safety study.
● The present research provided a platform for the development of safe cell-free strategy for disease treatment and will contribute to the subsequent development of high value-added industrialization of biotherapeutics and clinical application of effective regenerative medicine for a number of neurodegenerative diseases and other incurable disorders.
● As shown in this study, we can demonstrate other studies using various kinds of cells using constructed network, use this network to understand a properties of stem cells, find key regulators of transcriptional regulation using network, and we can develop some medicines or markers for purification using those found key regulators.
(출처 : SUMMARY 6p)
과제명(ProjectTitle) : | - |
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연구책임자(Manager) : | - |
과제기간(DetailSeriesProject) : | - |
총연구비 (DetailSeriesProject) : | - |
키워드(keyword) : | - |
과제수행기간(LeadAgency) : | - |
연구목표(Goal) : | - |
연구내용(Abstract) : | - |
기대효과(Effect) : | - |
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