Mini-Livers Derived from Human IPS Cells for Modeling Steatosis and Therapy
源自人类 IPS 细胞的微型肝脏用于脂肪变性建模和治疗
基本信息
- 批准号:8693277
- 负责人:
- 金额:$ 32.74万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2014
- 资助国家:美国
- 起止时间:2014-08-01 至 2018-07-31
- 项目状态:已结题
- 来源:
- 关键词:Animal ModelBile AcidsBile Duct EpitheliumBlood VesselsCell CommunicationCell modelCellsCessation of lifeCirrhosisCuesCultured CellsCytochrome P450DataDepositionDetectionDevelopmentDiseaseEarly DiagnosisElementsEmbryoEmploymentEngineeringEnvironmentEpithelial CellsEvolutionExhibitsFatty AcidsFatty LiverFatty acid glycerol estersFibrosisFutureGenesGenetic EngineeringGlycolysisGoalsHepaticHepatic TissueHepatocyteHomeostasisHumanHuman DevelopmentIn VitroInflammationInflammatoryInsulin ResistanceLeadLiverLiver DysfunctionLiver diseasesMediatingMessenger RNAMetabolicMetabolic DiseasesMetabolismMitochondriaModelingMolecularMusNatural HistoryOrganOrgan Culture TechniquesOrgan ModelPathogenesisPathway interactionsPhenotypePrevention approachPrimary carcinoma of the liver cellsProductionProteinsProtocols documentationPublic HealthRelative (related person)ResearchRoleStem cellsStudy modelsSystemTamoxifenTechniquesTechnologyTestingTherapeuticTimeTissue ModelTissuesTransplantationTriglyceridesWorkalternative treatmentbasecell typecellular engineeringdisease phenotypeimprovedinduced pluripotent stem cellinnovationlipid metabolismliver functionliver transplantationmacrophagenonalcoholic steatohepatitisnovel strategiespreventpublic health relevancescaffoldsmall hairpin RNAstemstem cell differentiationsuccessthree dimensional structuretool
项目摘要
ABSTRACT/SUMMARY
Our long-term goal is to develop a natural hepatic scaffold with multi-cellular cues for complete and stable
maturation of stem-derived liver cells to engineer functional livers in vitro and use them for modeling liver
steatosis and therapeutics. The objectives of the proposed study are to develop an organ culture system for
liver engineering with induced pluripotent stem (iPS) cell-derived liver cells, and investigate its employment to
understand pathogenesis, natural history and development of early detection tools and treatments for fatty liver
diseases. The central hypothesis to be tested here is that the decellularized natural liver scaffold can be
extensively repopulated, will provide a stable organ-like environment for the metabolic maturation of iPS
derived liver cells, and may be used as an approach to induce formation of functional mini-livers using human
wild type iPS cells or iPS cells after genetic engineer for fatty liver disease by knockdown of SIRT1 and/or (key
gene implicated with liver steatosis formation). The rationale for the proposed research is that, once human
liver tissue with multi-cellular cues can be reproducibly manufactured in vitro with normal and disease
phenotypes, development of liver steatosis can be manipulated pharmacologically, resulting in new and
innovative approaches to the prevention and treatment of a variety liver diseases. The work described here is
expected to i) generate a metabolic maturation system for human iPS cell-derived liver cells to form tissue, ii)
establish human iPS cells carrying shRNA mediated conditional knockdown of SIRT1 and iii) develop a novel
approach for modeling an organ-like environment to determine the role of SIRT1 in human liver steatosis or
fatty liver disease. The results of this work will also have a positive impact by establishing the basis and
platform for future sophisticated organ engineering techniques that incorporates several different cell types and
may lead to development of entire organs in vitro, these techniques could be applied to study other liver
diseases (e.g. metabolic diseases) and is expected to be a major contribution to the fields of stem cells
engineering and liver steatosis.
摘要/摘要
我们的长期目标是开发一种具有多细胞提示的天然肝支架,以实现完整和稳定的
干细胞来源的肝细胞在体外成熟以设计功能肝脏并用于肝脏建模
脂肪变性和治疗学。拟议研究的目标是开发一种器官培养系统,用于
诱导多能干细胞(IPS)来源的肝细胞进行肝脏工程,并探讨其在
了解脂肪肝的发病机制、自然历史及早期检测工具和治疗方法的发展
疾病。这里要检验的中心假设是,脱细胞的天然肝支架可以
广泛的再生,将为iPS的代谢成熟提供稳定的器官样环境
来源的肝细胞,并可能被用作一种方法,以诱导形成功能性迷你肝脏使用人
SIRT1和/或(Key)基因工程治疗脂肪肝后的野生型iPS细胞或iPS细胞
与肝脏脂肪变性形成有关的基因)。提出这项研究的理由是,一旦人类
具有多细胞信号的肝组织可以在体外正常和疾病情况下重复制造
肝脏脂肪变性的表型和发展可以通过药物控制,导致新的和
创新防治多种肝病的方法。这里描述的工作是
期望i)为人iPS细胞来源的肝细胞产生代谢成熟系统以形成组织,ii)
建立携带shRNA介导的SIRT1条件性敲除的人iPS细胞和III)开发一种新的
模拟器官样环境以确定SIRT1在人类肝脏脂肪变性或脂肪变性中的作用
脂肪肝。这项工作的结果也将产生积极影响,因为它建立了
未来复杂器官工程技术的平台,融合了几种不同的细胞类型和
可能导致整个器官的体外发育,这些技术可以应用于其他肝脏的研究
疾病(如代谢性疾病),预计将是对干细胞领域的重大贡献
工程学和肝脏脂肪变性。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(2)
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Alejandro Soto-Gutierrez其他文献
Alejandro Soto-Gutierrez的其他文献
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{{ truncateString('Alejandro Soto-Gutierrez', 18)}}的其他基金
Mini-Livers Derived from Human IPS Cells for Modeling Steatosis and Therapy
源自人 IPS 细胞的微型肝脏用于脂肪变性建模和治疗
- 批准号:
8897365 - 财政年份:2014
- 资助金额:
$ 32.74万 - 项目类别:
Mini-Livers Derived from Human IPS Cells for Modeling Steatosis and Therapy
源自人 IPS 细胞的微型肝脏用于脂肪变性建模和治疗
- 批准号:
9329289 - 财政年份:2014
- 资助金额:
$ 32.74万 - 项目类别:
Engineering of hepatic grafts with decellularized native matrices
使用脱细胞天然基质进行肝移植工程
- 批准号:
8508932 - 财政年份:2011
- 资助金额:
$ 32.74万 - 项目类别:
Engineering of hepatic grafts with decellularized native matrices
使用脱细胞天然基质进行肝移植工程
- 批准号:
8271008 - 财政年份:2011
- 资助金额:
$ 32.74万 - 项目类别:
Engineering of hepatic grafts with decellularized native matrices
使用脱细胞天然基质进行肝移植工程
- 批准号:
8333327 - 财政年份:2011
- 资助金额:
$ 32.74万 - 项目类别:
Engineering of hepatic grafts with decellularized native matrices
使用脱细胞天然基质进行肝移植工程
- 批准号:
7643685 - 财政年份:2009
- 资助金额:
$ 32.74万 - 项目类别:
Engineering of hepatic grafts with decellularized native matrices
使用脱细胞天然基质进行肝移植工程
- 批准号:
8000862 - 财政年份:2009
- 资助金额:
$ 32.74万 - 项目类别:
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