Characterization of embryonic stem cell-derived hematopoietic stem cells

胚胎干细胞来源的造血干细胞的表征

• 批准号: 7448120
• 负责人: SHANNON L MCKINNEY-FREEMAN
• 金额: $ 13.93万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-03-15 至 2013-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7448120
• 关键词: Achievement; Aorta; Biological Assay; Bone Marrow; Bone Marrow Transplantation; Boston; Cell surface; Cells; Cellular biology; Congenic Mice; Consultations; Cyclophosphamide/Doxorubicin/Etoposide/Prednisone/Vincristine; Data; Data Set; Derivation procedure; Development; Developmental Biology; Discrimination; Dissection; Educational workshop; Embryo; Erythroid; Erythroid Cells; Faculty; Fetal Liver; Fluorescence-Activated Cell Sorting; Future; Gene Expression; Genes; Glean; Goals; Gonadal structure; Hematology; Hematopoietic; Hematopoietic stem cells; Hemoglobin; Home environment; Laboratories; Life; Mentors; Mentorship; Mesonephric structure; Microarray Analysis; Molecular Profiling; Mus; PTPRC gene; Patients; Pattern; Pediatric Hospitals; Phenotype; Placenta; Population; Positioning Attribute; Postdoctoral Fellow; Procedures; Public Health; Publications; Research; Research Personnel; Role; Schools; Secure; Source; Staging; Stem Cell Research; Stem cells; Technical Expertise; Testing; Transplantation; Work; adult stem cell; base; career; cell type; embryonic stem cell; experience; in vivo; oncology; planetary Atmosphere; progenitor; programs; research study; skills

DESCRIPTION (provided by applicant): A 5-year plan is proposed in which the candidate will establish herself as an independent investigator in Stem Cell biology and further our understanding of hematopoietic stem cells generated by embryonic stem cells (ESC-HSC). In graduate school, the candidate developed an expertise in adult stem cells, focusing on HSC. As a postdoc, she furthered her expertise by researching the differentiative potential of ESC, initially exploring the role of the Cdx genes in hematopoietic development from ESC. This work is currently under review for publication. Her current research focuses on ESC-HSC. Although HSC were recently generated from ESC, nothing is known about their phenotype and function, especially in relation to in vivo HSCs. The candidate will test the hypothesis that ESC-HSC are akin to a developmentally immature in vivo HSC compartment by elucidating the phenotype of the ESC-HSC and comparing these cells functionally, by in vivo transplantation assays of HSC activity, and molecularly, via microarray analysis of global gene expression, to HSC purified from mice at different stages of in vivo development. This work will be conducted in the Division of Hematology/Oncology at Children's Hospital Boston under the mentorship of Dr. George Daley, a leader in stem cell biology. The Division is home to multiple laboratories renowned for their achievements in stem cell research (e.g. Drs. Stuart Orkin and Len Zon) and is a rich and collaborative atmosphere for advancing this field. To secure herself as an independent investigator and successfully complete the proposed work, the candidate must 1) expand her expertise in new fields pertinent to her research (e.g. Developmental Biology), 2) acquire new technical expertise (e.g. embryo dissection), and 3) develop the skills necessary to transition to an independent position (e.g. grantsmanship). Towards this end, after extensive consultation with her primary mentor, she has developed a personalized program composed of didactic and practical coursework, seminars and workshops, and a committee of experienced faculty who will meet with her semi-annually to guide her research and career development. The execution of this program, and the research aims outlined in this proposal, will allow the candidate to develop the expertise to establish herself as an independent and competitive investigator in ESC research. PUBLIC HEALTH RELEVANCE: Bone marrow transplantation (BMT) is extensively exploited for the treatment of hematopoietic maladies. Yet, many patients lack donors or must utilize non-ideal donors, resulting in life-threatening complications. Alternative sources of transplantable cells would greatly expand access to this life-saving procedure and minimize complications. Embryonic stem cells, with their capacity to generate any cell type, represent one hope for deriving an alternative cell source for BMT. The work out-lined in this proposal will significantly advance goal by increasing our understanding of cells isolated from embryonic stem cells.

描述（由申请人提供）： 提出了一个五年计划，其中候选人将成为干细胞生物学的独立研究者，并进一步加深我们对胚胎干细胞（ESC-HSC）产生的造血干细胞的理解。在研究生院，候选人发展了成体干细胞方面的专业知识，重点是 HSC。作为博士后，她通过研究 ESC 的分化潜力进一步拓展了自己的专业知识，最初探索了 Cdx 基因在 ESC 造血发育中的作用。这项工作目前正在审查出版中。她目前的研究重点是 ESC-HSC。尽管 HSC 最近是从 ESC 产生的，但对其表型和功能一无所知，特别是与体内 HSC 的关系。候选人将通过阐明 ESC-HSC 的表型并通过 HSC 活性的体内移植测定在功能上比较这些细胞，并通过整体基因表达的微阵列分析从分子上与从体内发育不同阶段的小鼠中纯化的 HSC 进行分子比较，来测试 ESC-HSC 类似于发育未成熟的体内 HSC 区室的假设。这项工作将在干细胞生物学领军人物 George Daley 博士的指导下在波士顿儿童医院血液学/肿瘤科进行。该部门拥有多个因在干细胞研究方面取得的成就而闻名的实验室（例如 Stuart Orkin 博士和 Len Zon 博士），并且为推进该领域提供了丰富的协作氛围。为了确保自己作为独立研究者并成功完成拟议的工作，候选人必须 1) 扩展与她的研究相关的新领域的专业知识（例如发育生物学），2) 获得新的技术专业知识（例如胚胎解剖），以及 3）培养过渡到独立职位所需的技能（例如资助）。为此，在与她的主要导师进行广泛协商后，她制定了一个个性化计划，包括教学和实践课程、研讨会和讲习班，以及一个由经验丰富的教师组成的委员会，该委员会将每半年与她会面一次，指导她的研究和职业发展。该计划的执行以及本提案中概述的研究目标将使候选人能够发展专业知识，使自己成为 ESC 研究中独立且有竞争力的研究者。 公共卫生相关性：骨髓移植 (BMT) 被广泛用于治疗造血系统疾病。然而，许多患者缺乏供体或必须使用不理想的供体，从而导致危及生命的并发症。可移植细胞的替代来源将极大地扩大这种挽救生命的手术的机会并最大限度地减少并发症。胚胎干细胞具有产生任何细胞类型的能力，代表着为 BMT 提供替代细胞来源的希望。该提案中概述的工作将通过增加我们对从胚胎干细胞中分离的细胞的了解来显着推进目标。