Elucidating the role of DCAF7 on hematopoietic stem cell maintenance

项目摘要 造血干细胞(HSC)的功能已在遗传和表型水平上进行了详细的研究， 但是，翻译后修饰，特别是泛素化，如何影响它们的活性，构成了 知识。 因此，迫切需要更好地了解HSC泛素连接酶的功能 ，这是 代表着有吸引力的药物发现目标。泛素连接酶相关蛋白DCAF7(DDB1和CUL4 相关因子7)在造血干细胞中高表达，该基因的突变在髓系疾病中被发现。 研究DCAF7在造血中的作用与了解泛素化如何调控HSC功能有关 以及它的失调如何导致骨髓衰竭和恶性肿瘤。我的初步数据显示 在小鼠胚胎中删除Daf7会导致出生小鼠数量显著减少，并导致Daf7丢失 在成年小鼠中，HSC的自我更新和分化受到损害。因此，我的假设是DCAF7是一个必不可少的 通过调节蛋白平衡和分化基因的表达来调节造血。我的建议 研究将通过两个特定的目的来研究DCAF7在造血中的作用：1)确定DCAF7是如何 丢失影响胎儿和成人环境中的HSC功能；2)研究 DCAF7对HSC功能有调节作用。最终，我的研究将提供对生理学的基本见解 DCAF7的功能与新的造血调控分子机制的发现。这项研究 将在圣犹大儿童研究医院在克里斯皮诺博士的指导下完成 由该领域的专家组成的委员会。这个K01职业发展奖将是扩展我的职业生涯和 制定造血基础科学的研究计划。这将使我能够实现我的研究目标 并成功过渡，成立了自己的研究小组。此外，它将为我提供 有机会得到干细胞生物学、表观遗传学和泛素化方面的领先专家团队的指导。AS 作为培训的一部分，我还将参加一些活动，以增强我的领导力、写作和口头陈述 技能。这些概念和技术专长以及专业发展的额外领域将是 既需要完成提案，又需要建立运行自己的研究小组所需的技能。

Project Summary The function of Hematopoietic stem cells (HSC) has been studied in detail at the genetic and phenotypic level, but how posttranslational modifications, specifically ubiquitination, affect their activity constitutes a gap in knowledge. There is therefore a critical need to better understand the function of HSC ubiquitin ligases , which represent attractive targets for drug discovery. The ubiquitin ligase-associated protein DCAF7 (DDB1 And CUL4 Associated Factor 7) is highly expressed in HSCs, and mutations in the gene are found in myeloid disorders. Studying DCAF7 function in hematopoiesis is relevant to understanding how ubiquitination controls HSC function and how its dysregulation contributes to bone marrow failure and malignancies. My preliminary data show that deletion of Dcaf7 in mouse embryos results in a significantly lower number of mice born, and that loss of Dcaf7 in adult mice impairs HSC self-renewal and differentiation. Thus, my hypothesis is that DCAF7 is an essential regulator of hematopoiesis by modulating proteostasis and expression of differentiation genes. My proposed studies will investigate the role of DCAF7 in hematopoiesis through two specific aims: 1) Determine how DCAF7 loss affects HSC function in fetal and adult environments and 2) Investigate the molecular mechanisms by which DCAF7 regulates HSC function. Ultimately, my studies will provide fundamental insights into the physiologic functions of DCAF7 and the discovery of novel molecular mechanisms regulating hematopoiesis. This research will be completed at St. Jude Children’s Research Hospital under the guidance of Dr. Crispino and an advisory committee with experts in the field. This K01 Career Development Award will be critical to expand my career and develop a research program in basic science of hematopoiesis. It will enable me to achieve my research goals and making a successful transition to establish my own research group. Furthermore, it will provide me the opportunity to be mentored by a team of leading experts in stem cell biology, epigenetics, and ubiquitination. As part of my training, I will also participate in activities to enhance my leadership, writing and oral presentation skills. These additional areas of conceptual and technical expertise and professional development will be required to both complete the proposal and establish the skills necessary to run my own research group.