DNA Methylation Control Hematopoietic Stem Cell Lineage Differentiation

候选人： 我曾在贝勒大学玛格丽特·古德尔教授的实验室担任博士后研究员， 医学（休斯顿，德克萨斯州）三年，来自博士学位。在昆士兰州大学（布里斯班， 澳大利亚昆士兰州），2006年5月。我从澳大利亚NHMRC获得了第一笔奖学金， 在我两年的博士后期间，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。我现在申请更高级的 奖学金，并开始采取初步措施，建立自己的研究计划。的时机 这份申请代表了我职业生涯的一个十字路口，我开始向独立过渡 开始我自己的研究项目 我在理解造血干细胞的分子调控方面的工作是由一个 我渴望改善造血系统疾病患者的生活，我的最终职业目标是 看到HSC生物学中有意义的发现的实施，以帮助推动新的临床结果。我 我相信，这项提案中概述的工作最终可能会导致新的治疗方法， 患者范围广泛。获得NIH独立之路奖（K99/R 00）将使我获得 在该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前沿技术。 通过额外的培训，我将能够在一家排名靠前的公司从事独立的研究工作。 学术和研究环境，重点是独立期间的翻译研究 奖的阶段。 我的职业目标在指导阶段的赠款包括出版三个第一作者的论文 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， 完成职业发展活动，以提高我的科学背景。我的长期职业生涯 在赠款的指导阶段的目标包括建立一个成功的独立研究 计划，在高影响力期刊上发表高级作者，并通过 NIH R 01或其他机制。最后，我希望我的工作能对世界做出重大贡献。 理解HSC生物学及其与人类疾病状态的相关性，并将我的研究结果转化为 研究新的临床治疗策略。 工作环境： 贝勒医学院（Baylor College of Medicine）是一所致力于研究的一流研究机构， 解开人体的奥秘，寻找治疗疾病和改善健康的新方法。作为 细胞和基因治疗中心（CAGT）和干细胞和再生医学中心的一部分 （星星）中心，我将有机会获得不同的核心设施，在微阵列，流式细胞术， 显微镜和胚胎干细胞以及获得高水平，无病原体的屏障， 带有限制访问安全系统的通风机架。此外，教师的不同利益， 这些中心包括造血，干细胞生物学，造血干细胞移植，基因 治疗，免疫治疗和载体开发，并提供了充分的合作机会，以进一步 我的科学训练。 研究： 从我的博士后工作，我已经确定了一个项目，关于DNA甲基化的作用， 造血干细胞（HSC）谱系命运特化。我已经确定 DNA甲基转移酶在HSC亚型之间的表达，骨髓偏向性HSC 表达更高水平的Dnmt 3a和具有更高表达的Dnmt 3b的淋巴偏向性HSC，以及I 假设HSC谱系命运决定至少部分地由DNA的作用控制， 甲基转移酶在这项研究中，我建议检查DNA甲基转移酶的功能影响， HSC中的Dnmt 3a和Dnmt 3b。这里提出的实验将揭示DNA的作用 甲基化在HSC功能中的作用，并开始揭示调节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 research.此外，有充分的证据表明，异常的DNA甲基化有助于在一些， 对包括某些造血系统疾病在内的各种人类疾病的治疗方法尚未确定。我相信 本项目中概述的基础研究有助于对表观遗传的基本理解。 调节干细胞功能，并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.