DNA Methylation Control Hematopoietic Stem Cell Lineage Differentiation

候选人： 我一直是贝勒学院玛格丽特·古德尔教授实验室的博士后研究员。 医学(德克萨斯州休斯敦)，三年，毕业于昆士兰大学(布里斯班， 澳大利亚昆士兰)，2006年5月。我从澳大利亚NHMRC获得了最初的奖学金，以资助第一个 我做了两年博士后，在此期间我研究了造血干细胞的分子调控 分化和控制干细胞命运的表观遗传机制。我现在正在申请更高年级的 奖学金，并开始采取初步步骤，建立自己的研究计划。时间的选择 这份申请代表着我职业生涯的十字路口，我正开始向独立过渡 并启动我自己的研究项目。 我在理解造血干细胞的分子调控方面的工作是由一种 渴望改善患有造血疾病的患者的生活，我的最终职业目标是 了解HSC生物学中有意义的发现的实施情况，以帮助推动新的临床结果。我 相信这项提案中概述的工作最终可能导致新的治疗方法 病人的范围很广。获得NIH独立之路奖(K99/R00)将使我获得 在奖项的指导阶段进行额外的研究培训，并在职业生涯中概述活动 发展部门，如研讨会、期刊俱乐部、科学会议、研究方面的额外培训 技术和教学课程，以及接触干细胞生物学的尖端技术。 通过额外的培训，我将能够在一个排名很高的职位上追求独立的研究职位 学术和研究环境，在独立期间强调翻译研究 颁奖阶段。 在基金的指导阶段，我的职业目标包括发表三篇第一作者论文 在高影响力的期刊上，学习表观遗传学和计算生物学的研究技术，以及 完成职业发展活动，提升我的科学背景。我长期的职业生涯 资助指导阶段的目标包括建立一项成功的独立研究 计划，作为高级作者在影响较大的期刊上发表文章，并通过以下方式获得独立资金 美国国立卫生研究院R01‘S等机制。最终，我希望我的工作能为 了解HSC生物学及其与人类疾病状态的相关性，并将我的研究结果 研究新的临床治疗策略。 环境： 贝勒医学院(BCM)是一家致力于研究、 解开人体的奥秘，找到治愈疾病和改善健康的新方法。AS 细胞和基因治疗中心(CAGT)以及干细胞和再生医学中心的一部分 (STAR)中心，我将有机会接触到各种核心设施，拥有基因芯片、流式细胞仪、 显微镜和胚胎干细胞以及获得高水平、无病原体的屏障利用 通风机架，门禁安全系统。此外，该学院教职员工的不同兴趣 这些中心包括造血学、干细胞生物学、造血干细胞移植、基因 治疗、免疫治疗和媒介开发，并为进一步合作提供了充分的机会 我的科学训练。 研究： 从我的博士后工作中，我确定了一个关于DNA甲基化在 造血干细胞(HSC)谱系命运规范。我已经确定两者之间存在差异 骨髓偏向HSC亚型间DNA甲基转移酶的表达 表达较高水平的DNMT3A和偏向淋巴的HSC具有较高的DNMT3b表达，以及 假设HSC血统命运至少部分由DNA的作用控制 甲基转移酶。在这项研究中，我建议研究DNA甲基转移酶的功能效应。 HSC中的DNMT3A和DNMT3B。这里提出的实验将为dna的作用提供新的线索。 HSC功能中的甲基化，并开始揭示调控干细胞生物学的表观遗传机制。 越来越多的证据表明表观遗传机制在基因调控中的重要性。 转录和正常细胞功能，这一研究领域代表了干细胞的下一个主要问题 研究。此外，有充分的证据表明，异常的DNA甲基化在某些AS中起作用。 各种人类疾病的致病途径尚未明确，包括某些血液系统疾病。我相信 本项目概述的基础研究有助于对表观遗传学的基本理解。 干细胞功能的调节，与人类疾病状态的进展直接相关。

Candidate: I have been a post-doctoral researcher in the lab of Prof. Margaret Goodell at Baylor College of Medicine (Houston, TX) for three years, coming from a Ph.D. at the University of Queensland (Brisbane, QLD, Australia) in May, 2006. I obtained an initial fellowship from the Australian NHMRC to fund the first two years of my post-doc, during which I have studied the molecular regulation of hematopoietic stem cell differentiation and the epigenetic mechanisms that control stem cell fate. I am now applying for more senior fellowships and beginning to take the initial steps to establishing my own research programs. The timing of this application represents a crossroads in my career, where I am beginning to transition to independence and initiate my own research programs. My work in understanding the molecular regulation of hematopoietic stem cells is motivated by a desire to improve the lives of patients afflicted with hematopoietic disorders and my ultimate career goal is to see the implementation of meaningful discoveries in HSC biology to help drive novel clinical outcomes. I believe that the work outlined in this proposal could ultimately lead to novel therapeutic approaches for a wide range of patients. Obtaining an NIH Pathway to Independence Award (K99/R00) will allow me to gain additional research training in the mentored phase of the award with activities outlined in the career development section such as seminars, journal clubs, scientific conferences, additional training in research techniques and didactic coursework as well as exposure to cutting edge techniques in stem cell biology. With additional training, I will be able to pursue an independent research position in a highly ranked academic and research environment with an emphasis in translational research during the independent phase of the award. My career goals during the mentored phase of the grant include publishing three first-author papers in high-impact journals, learning research techniques in epigenetics and computational biology and completing the career development activities to enhance my scientific background. My long-term career goals during the mentored phase of the grant include establishment of a successfully independent research program, publishing as a senior author in high-impact journals and obtaining independent funding through NIH R01's or other mechanisms. Ultimately, I would like my work to make a significant contribution to the understanding of HSC biology and its relevance to human disease states and to translate findings from my research into novel clinical treatment strategies. Environment: Baylor College of Medicine (BCM) is a premier research institute that is committed to research, unraveling the mysteries of the human body, and finding new ways to cure disease and improve health. As part of the Center for Cell and Gene Therapy (CAGT) and the Stem Cells and Regenerative Medicine (STaR) Center, I will have access to diverse core facilities with expertise in microarray, flow cytometry, microscopy and embryonic stem cells as well as access to a high-level, pathogen-free barrier utilizing ventilated racks with a limited access security system. Moreover, the diverse interests of the faculty of these Centers includes hematopoiesis, stem cell biology, hemopoietic stem cell transplantation, gene therapy, immunotherapy, and vector development and provides ample opportnity for collaboration to further my scienific training. Research: From my post-doctoral work, I have identified a project concerning the role of DNA methylation in hematopoietic stem cell (HSC) lineage fate specification. I have determined that there is differential expression of DNA methyltransferase enzymes between HSC subtypes, with myeloid-biased HSCs expressing higher levels of Dnmt3a and lymphoid-biased HSCs having higher expression of Dnmt3b, and I hypothesize that HSC lineage fate determination is at least partly controlled by the actions of DNA methyltransferases. In this study I propose to examine the functional effects of the DNA methyltransferases Dnmt3a and Dnmt3b in HSCs. The experiments proposed here will shed new light on the role of DNA methylation in HSC function and begin to uncover the epigenetic mechanisms regulating stem cell biology. There is mounting evidence for the importance of epigenetic mechanisms in the regulation of gene transcription and normal cell function, and this field of study represents the next major question in stem cell research. Moreover, there is ample evidence suggesting aberrant DNA methylation contributes in some as of yet undefined ways to various human diseases including certain hematopoietic disorders. I believe the basic research outlined in this project can contribute to the fundamental understanding of epigenetic regulation of stem cell function and has direct relevance to progression of human disease states.