Multipotent heart cell progenitor lineages in cardiac development and disease
心脏发育和疾病中的多能心脏细胞祖细胞谱系
基本信息
- 批准号:7677126
- 负责人:
- 金额:$ 4.2万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2008
- 资助国家:美国
- 起止时间:2008-12-01 至 2009-05-31
- 项目状态:已结题
- 来源:
- 关键词:AutologousCardiacCardiac MyocytesCardiovascular systemCell TherapyCellsChemical AgentsClinicalColorCommitDevelopmentDiseaseEmbryoFamilyFibroblastsFilmFunctional disorderGenerationsGenesGeneticHealthHeartHeart DiseasesHeart failureHumanIndividualIslets of LangerhansLaboratoriesModelingMolecularMusMuscleMutationMyocardiumPathway interactionsPatientsPluripotent Stem CellsProtocols documentationReagentReporterSkinSourceSystemTherapeuticTissue Engineeringbasebeta catenincell typeembryonic stem cellheart cellhuman embryonic stem cellimprovedisletmyogenesisnovelprecursor cellprogenitorself-renewalstemstem cell biologystem cell technologytool
项目摘要
DESCRIPTION (provided by applicant): The identification of an optimal cell type to drive robust cardiac myogenesis is critical for improving cell-based therapy and to develop human cardiomyocyte models for heart failure. Recent studies in the Chien lab have allowed the identification, purification, and renewal of multipotent Islet-1 cardiovascular progenitors from both murine and human embryonic stem (ES) cells and inducible pluripotent stem cells (iPS). Utilizing a novel two color reporter system, a unique subset of completely committed, self-renewing cardiomyogenic progenitors (CMPs) have been isolated from ES cells, and used to generate thin films of cardiac muscle via tissue engineering. The Melton lab has recently developed novel protocols for the high efficiency generation of iPS cells from murine and human skin fibroblasts using just two genes and a chemical agent, while the Chien/Wu labs have effectively purified heart progenitors from iPS cell sources, documenting the feasibility for generating autologous human cardiovascular progenitors from iPS sources from an individual patient for cell based therapy and/or for the generation of human cardiac muscle cell-based models of cardiac disease, which should allow the use of an arsenal of genetic tools to identify the molecular pathways for cardiac muscle dysfunction. This proposal integrates unique expertise, reagents, and protocols from three leading laboratories: heart stem cell biology in development and disease (Chien); human ES and iPS technology (Melton); and cardiac muscle tissue engineering (Kit Parker). Accordingly, the Specific Aims of the two proposed projects are: Project 1: Multi-potent Islet-1/Nkx2.5 heart cell progenitors and the formation, renewal, and differentiation of committed cardiomyogenic progenitor (CMP) lineages: 1) Characterization of committed cardiomyogenic progenitors(CMPs) of the Islet-1/Nkx2.5 family of heart progenitors; 2) Generation of functional heart muscle strips from CMPs of the Islet-1/Nkx2.5 family of heart progenitors; 3) Identification of Pathways which drive the formation, renewal, survival, and differentiation of committed cardiomyogenic progenitors of the Islet-1/Nkx2.5 family (Wnt/Beta Catenin, Creb312, etc.); 4) Identification, purification, and characterization of the conduction system progenitors of the Islet-1/Nkx2.5 family of heart progenitors; Project 2: Generation of mouse and human heart progenitor derived models of human cardiac diseases: 1) Purification and characterization of human multipotent Islet-1/Nkx2.5 progenitors and their cardiomyogenic lineages derived from human ES and iPS cells; 2) Generation and characterization of functional mouse and human heart muscle strips from multipotent Islet-1/Nkx2.5 progenitors and their cardiomyogenic lineages derived from ES and iPS cells; 3) Generation and characterization of murine and human heart muscle strips from ES and iPS cells that harbor cardiomyopathic mutations. .
描述(由申请人提供):确定驱动强健心肌生成的最佳细胞类型对于改进基于细胞的治疗和开发心力衰竭的人类心肌细胞模型至关重要。简实验室最近的研究已经允许从小鼠和人类胚胎干细胞(ES)细胞和诱导多能干细胞(iPS)中鉴定、纯化和更新多能胰岛-1心血管祖细胞。利用一种新的双色报告系统,从胚胎干细胞中分离出一种独特的完全承诺的、自我更新的心肌生成祖细胞(cmp),并通过组织工程用于生成心肌薄膜。Melton实验室最近开发了新的方案,利用两个基因和一种化学试剂,从小鼠和人类皮肤成纤维细胞中高效地生成iPS细胞,而Chien/Wu实验室则从iPS细胞来源中有效地纯化了心脏祖细胞。记录了从个体患者的iPS来源中产生自体人类心血管祖细胞用于细胞治疗和/或生成基于人类心肌细胞的心脏病模型的可行性,这将允许使用一系列遗传工具来识别心肌功能障碍的分子途径。该提案整合了来自三个领先实验室的独特专业知识、试剂和方案:发育和疾病中的心脏干细胞生物学(Chien);人类胚胎干细胞和iPS技术(Melton);以及心肌组织工程学(Kit Parker)。因此,两个拟议项目的具体目标是:项目1:多能胰岛-1/Nkx2.5心脏细胞祖细胞和承诺的心肌祖细胞(CMP)谱系的形成、更新和分化;1)胰岛-1/Nkx2.5心脏祖细胞家族的承诺的心肌祖细胞(CMP)的表征;2)心脏祖细胞Islet-1/Nkx2.5家族CMPs生成功能性心肌条带;3)胰岛-1/Nkx2.5家族(Wnt/Beta Catenin, Creb312等)心肌祖细胞形成、更新、存活和分化的途径鉴定;4)心脏祖细胞Islet-1/Nkx2.5家族传导系统祖细胞的鉴定、纯化和表征;项目二:人类心脏疾病小鼠和人类心脏祖细胞衍生模型的建立:1)人类多能胰岛1/Nkx2.5祖细胞的纯化和鉴定及其源自人类ES和iPS细胞的心肌形成谱系;2)多能胰岛素-1/Nkx2.5祖细胞及其ES和iPS细胞的心肌系的制备和鉴定;3)利用含有心肌病突变的ES和iPS细胞制备和表征小鼠和人心肌条带。
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(0)
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KENNETH R CHIEN其他文献
KENNETH R CHIEN的其他文献
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{{ truncateString('KENNETH R CHIEN', 18)}}的其他基金
Characterization of Cardiac Progenitors Derived from 22q11-deleted Patients
22q11 缺失患者心脏祖细胞的表征
- 批准号:
7818254 - 财政年份:2009
- 资助金额:
$ 4.2万 - 项目类别:
Human Pluripotent Stem Cell and Progenitor Models of Cardiac and Blood Diseases
人类多能干细胞和心脏和血液疾病的祖细胞模型
- 批准号:
7939716 - 财政年份:2009
- 资助金额:
$ 4.2万 - 项目类别:
Characterization of Cardiac Progenitors Derived from 22q11-deleted Patients
22q11 缺失患者心脏祖细胞的表征
- 批准号:
7933892 - 财政年份:2009
- 资助金额:
$ 4.2万 - 项目类别:
Human Pluripotent Stem Cell and Progenitor Models of Cardiac and Blood Diseases
人类多能干细胞和心脏和血液疾病的祖细胞模型
- 批准号:
8113929 - 财政年份:2009
- 资助金额:
$ 4.2万 - 项目类别:
Human Pluripotent Stem Cell and Progenitor Models of Cardiac and Blood Diseases
人类多能干细胞和心脏和血液疾病的祖细胞模型
- 批准号:
7833974 - 财政年份:2009
- 资助金额:
$ 4.2万 - 项目类别:
Cytoskeletal-Associated Proteins and Cardiomyopathy
细胞骨架相关蛋白和心肌病
- 批准号:
7226311 - 财政年份:2005
- 资助金额:
$ 4.2万 - 项目类别:
Cytoskeletal-Associated Proteins and Cardiomyopathy
细胞骨架相关蛋白和心肌病
- 批准号:
7114922 - 财政年份:2005
- 资助金额:
$ 4.2万 - 项目类别:
Cytoskeletal-Associated Proteins and Cardiomyopathy
细胞骨架相关蛋白和心肌病
- 批准号:
7480264 - 财政年份:2005
- 资助金额:
$ 4.2万 - 项目类别:
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