Transcriptional regulation of hematopoietic stem cell fate during aging and bone marrow failure

衰老和骨髓衰竭过程中造血干细胞命运的转录调控

• 批准号: 9549041
• 负责人: Britta Will
• 金额: $ 5.8万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE, INC
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-22 至 2018-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9549041
• 关键词: AT Rich Sequence; Acute Myelocytic Leukemia; Address; Adult; Age; Aging; Applications Grants; Award; Binding; Binding Proteins; Cell Aging; Cell Line; Cell Proliferation; Cell physiology; Cells; Cellular biology; Chromatin; Collaborations; Colony-Forming Units Assay; Computer Analysis; Cytosine; DNA; Data; Data Analyses; Detection; Development; Disease; Dysmyelopoietic Syndromes; Educational workshop; Elderly; Environment; Epigenetic Process; Faculty; Failure; Fostering; Funding; Gene Expression; Gene Targeting; Gene Transfer; Genes; Genetic; Genetic Models; Genetic Transcription; Goals; Grant; Growth; Hematological Disease; Hematopoiesis; Hematopoietic System; Hematopoietic stem cells; Homeostasis; Human; Impairment; Individual; Institution; Instruction; Knockout Mice; Laboratories; Life; Lymphoid; Maintenance; Malignant - descriptor; Malignant Neoplasms; Marrow; Mediating; Medicine; Mentored Research Scientist Development Award; Mentors; Methylation; Molecular; Mus; Mutation; Myelogenous; Myeloid Leukemia; New York City; Pancytopenia; Pathogenesis; Pathway interactions; Patients; Pattern; Persons; Phenotype; Play; Population; Positioning Attribute; Postdoctoral Fellow; Predisposition; Premature aging syndrome; Process; Proteins; RNA; Regulation; Regulator Genes; Research; Research Personnel; Research Training; Residual state; Role; Source; Stem Cell Development; Stem cells; Testing; Therapeutic Intervention; Time; Tissues; Training; Transcriptional Regulation; Work; Writing; adult stem cell; age related; aged; base; bone marrow failure syndrome; career; career development; cell age; cell type; college; deep sequencing; design; experience; experimental study; hematopoietic stem cell fate; human model; in vivo; innovation; leukemia; meetings; member; methylation pattern; mouse model; mutant; next generation sequence data; next generation sequencing; novel; novel therapeutic intervention; novel therapeutics; overexpression; post-doctoral training; programs; public health relevance; repaired; restoration; self-renewal; stem; stem cell fate; symposium; tissue regeneration; transcription factor; virtual

 DESCRIPTION (provided by applicant): During her postdoctoral training in Dr. Ulrich Steidl's laboratory in the Department of Cell Biology at the Albert Einstein College of Medicine, Dr. Will has independently and successfully initiated a line of research focusing on the molecular regulation of adult tissue-specific stem cell self-renewal and differentiation commitment. Her work has uncovered a novel central role for a particular transcription factor, Special AT- rich sequence-binding protein 1 (Satb1), in the maintenance of gene expression programs and DNA cytosine methylation patterns, which govern hematopoietic stem cell (HSC) function. Under the guidance of her mentoring committee and with the help of carefully selected and dedicated expert collaborators and advisers, Dr. Will will focus on reaching her short-term career goals for the duration of the award. Her proposal is thus tailored to meet the following specific experimental research and associated training objectives: * To identify and functionally test Satb1-dependent gene networks, particularly the ones regulating myeloid and lymphoid differentiation commitment of HSCs and to evaluate their contribution to age-related myelodysplastic syndrome; * To assess the requirement for myeloid-biased HSCs in the pathogenesis of aging and in aging- associated myelodysplasia using murine models and human primary cells; * To extend her experience in designing and conducting RNA isolation, chromatin immunoprecipation and DNA cytosine methylation detection followed by deep sequencing using primary HSCs and HSC cell lines; and to get profound training in the computational analysis of NGS data analysis; * To foster existing and establish new collaborations, especially in the field of aging research; * To generate exciting data suitable to produce grant proposals; * To obtain independent R01(-type) funding at the end of the award. In order to meet these milestones, the candidate will take advantage of the outstanding state-of-the-art research and training environment at the Albert Einstein College of Medicine, both at the departmental and the institutional level, and of well-established ongoing collaborative efforts of Dr. Steidl and several established investigators at other New York City-based institutions. This is made possible through the retention of Dr. Will as a junior, non tenure-track faculty member in the Department of Cell Biology for the next five years. Dr. Will will advance her focused training for developing her independent research by engaging in one-on-one meetings with her mentors and collaborators, relevant coursework, scientific research seminars and symposia, intra-and extra-institutional career development and grant writing workshops. Additionally, she will profit greatly from speaking opportunities at her and other NYC-based institutions, and at scientific meetings. Upon completion of the award, the candidate will be able to address her long-term career goals, which are: * To establish a long-term research program addressing relevant questions in the fields of stem cell and aging research; * To further build her own research group and to obtain a position as an independent investigator at an academic institution. To this end, acquired and further strengthened abilities under the K01 award will provide Dr. Will with the critically needed conceptual and technical framework to successfully establish her independent research pipeline. Ultimately, Dr. Will's research will provide a much more profound understanding of the gene expression-regulating and potentially reversible processes underlying stem cell aging, which can be leveraged for fundamentally novel therapeutic approaches in hematopoietic stem cell-derived disorders in the elderly.

 描述（由适用提供）：威尔博士在阿尔伯特·爱因斯坦医学院的乌尔里希·斯蒂德（Ulrich Steidl）博士在细胞生物学系的实验室实验室进行博士后培训期间，威尔博士独立而成功地启动了一系列研究，重点介绍了成人组织特异性干细胞细胞自我恢复和分化承诺的分子调节。她的工作发现了特定转录因子（特殊的AT-序列结合蛋白1（SATB1））在维持基因表达程序和DNA胞质甲基化模式中的新型核心作用，该蛋白质表达程序和DNA胞质甲基化模式负责造血干细胞（HSC）功能。在她的心理委员会的指导下，并在精心挑选和敬业的专家合作者和顾问的帮助下，威尔·威尔（Will Will）将专注于在奖项期间实现她的短期职业目标。因此，她的建议是为了满足以下特定的实验研究和相关培训目标的量身定制的： *识别并在功能上测试SATB1依赖性基因网络，尤其是调查HSC的髓样和淋巴样分化承诺的基因网络，并评估其对年龄相关的骨髓增生性骨髓增生性综合征的贡献； *使用鼠模型和人类原代细胞评估在衰老的发病机理和衰老相关的骨髓增生性的发病机理中对髓样偏置的HSC的需求； *为了扩展她在设计和进行RNA隔离方面的经验，染色质免疫和DNA胞嘧啶甲基化检测，然后使用原代HSC和HSC细胞系进行深层测序；并在NGS数据分析的计算分析中获得深刻的培训； *促进现有并建立新的合作，尤其是在衰老研究领域； *生成适合生成赠款建议的令人兴奋的数据； *在奖励结束时获得独立的R01（-Type）资金。为了达到这些里程碑，候选人将利用艾伯特·爱因斯坦医学院的最先进的研究和培训环境，包括部门和机构一级，以及Steidl博士和纽约市其他基于纽约市的几项研究人员的合作努力。通过保留威尔博士，成为细胞生物学系的初级，非任期教师，这是通过保留威尔博士的。威尔博士将通过与她的导师和合作者，相关课程，科学研究仪式和专题讨论会，内部和额外机构的职业发展以及授予写作研讨会的一对一会议，并与她的指导者和合作者，相关课程，科学研究中心和座谈会进行一对一的会议，以推进她的重点培训，以发展自己的独立研究。此外，她将从她和其他纽约市的机构以及在科学会议上发表讲话的机会。颁奖典礼完成后，候选人将能够解决她的长期职业目标，这是： *建立一项长期研究计划，以解决干细胞和衰老研究领域的相关问题； *进一步建立自己的研究小组，并在学术机构担任独立研究者的职位。为此，根据K01奖获得的获得并进一步增强了能力，将为Will博士提供迫切需要的概念和技术框架，以成功建立她的独立研究管道。最终，Will博士的研究将为干细胞衰老的基因表达调节和潜在可逆过程提供更深刻的了解，这些过程可以利用造血干细胞衍生的疾病的根本新型热方法来利用。