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

 描述(申请人提供)：在阿尔伯特·爱因斯坦医学院细胞生物学系Ulrich Steidl博士的实验室接受博士后培训期间，Will博士独立并成功地启动了一系列研究，重点是成人组织特定干细胞自我更新和分化承诺的分子调控。她的工作揭示了一种特殊的转录因子，特殊的AT丰富的序列结合蛋白1(Satb1)在维持基因表达程序和DNA胞嘧啶甲基化模式中的新核心作用，这些模式控制着造血干细胞(HSC)的功能。在她的指导委员会的指导下，在精心挑选和专注的专家合作者和顾问的帮助下，威尔博士将专注于在获奖期间实现她的短期职业目标。因此，她的建议是为满足以下特定的实验研究和相关的培训目标而量身定做的：*识别并从功能上测试依赖Satb1的基因网络，特别是调节造血干细胞的髓系和淋巴分化承诺的基因网络，并评估它们在年龄相关骨髓增生异常综合征中的作用；*利用小鼠模型和人类原代细胞，评估偏髓系造血干细胞在衰老发病机制和衰老相关骨髓发育不良中的需求；*扩大她在设计和进行RNA分离、染色质免疫沉淀和DNA胞嘧啶甲基化检测方面的经验，然后使用原始HSC和HSC细胞系进行深度测序；以及在NGS数据分析的计算分析方面接受深入培训；*促进现有的合作并建立新的合作，特别是在老龄化研究领域；*产生令人兴奋的数据，适合提出拨款建议；*在奖项结束时获得独立的R01(类型)资金。为了达到这些里程碑，候选人将利用阿尔伯特·爱因斯坦医学院优秀的最先进的研究和培训环境，包括院系和机构层面，以及施泰德博士和纽约其他机构的几名资深研究人员正在进行的良好合作努力。这是通过在接下来的五年里保留威尔博士作为细胞生物系初级、非终身教职的教员而实现的。威尔博士将通过参加与她的导师和合作者的一对一会议、相关课程、科学研究研讨会和专题讨论会、机构内外职业发展和拨款撰写研讨会来推进她的重点培训，以发展她的独立研究。此外，她还将从她和纽约其他机构以及科学会议上的演讲机会中获益良多。在完成该奖项后，候选人将能够实现她的长期职业目标，即：*建立一个长期研究计划，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，并在一家学术机构获得独立研究员的职位。为此，在K01奖项下获得并进一步加强的能力将为威尔博士提供急需的概念和技术框架，以成功建立她的独立研究渠道。最终，威尔博士的研究将对干细胞老化背后的基因表达调控和潜在的可逆过程提供更深刻的理解，这些过程可以被用于老年人造血干细胞衍生疾病的根本性新型治疗方法。

 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.