Elucidating the role of DCAF7 on hematopoietic stem cell maintenance

阐明 DCAF7 对造血干细胞维持的作用

• 批准号: 10785443
• 负责人: Johanna Melo-Cardenas
• 金额: $ 13.45万
• 依托单位: ST. JUDE CHILDREN'S RESEARCH HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-15 至 2028-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10785443
• 关键词: Adult; Advisory Committees; Affect; Apoptosis; Area; Basic Science; Binding; Biochemical; Birth; Blood; Bone Marrow Cells; Bone marrow failure; Cell Cycle; Cell Death; Cell Line; Cell Maintenance; Cells; Chromatin; Complex; Cullin Proteins; Data; Development; Differentiated Gene; Disease; Drug Targeting; Embryo; Environment; Epigenetic Process; Fetal Liver; Future; Gene Expression; Genes; Genetic; Genetic Transcription; Goals; Hematological Disease; Hematology; Hematopoiesis; Hematopoietic; Hematopoietic stem cells; Image; Immunophenotyping; Impairment; In Vitro; Investigation; K-Series Research Career Programs; Kinetics; Knowledge; Leadership; Ligase; Maintenance; Malignant Neoplasms; Measures; Mediating; Mentors; Modification; Molecular; Mus; Mutation; Myelogenous; Oral; PRC1 Protein; Phenotype; Physiological; Play; Population Dynamics; Post-Translational Protein Processing; Proteins; Proteomics; Recovery; Research; Role; Running; Saint Jude Children' s Research Hospital; Stress; Substrate Specificity; System; Technical Expertise; Testing; Time; Training; Transplantation; Ubiquitin; Ubiquitination; Writing; blood treatment; career; chemotherapy; drug discovery; fetal; hematopoietic stem cell differentiation; hematopoietic stem cell self-renewal; in vivo; insight; mouse model; novel; progenitor; programs; protein degradation; proteostasis; public health relevance; self-renewal; single-cell RNA sequencing; skills; stem; stem cell biology; stem cell division; stem cell function; transcriptome sequencing; ubiquitin ligase; ubiquitin-protein ligase; ubiquitinated H2A

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.

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研究， 但是，翻译后修饰（特别是泛素化）如何影响其活动构成差距 知识。 因此，迫切需要更好地了解HSC泛素连接酶的功能 ， 哪个 代表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HSC中高度表达，并且基因中的突变在髓样疾病中发现。 在造血中研究DCAF7功能与了解泛素化如何控制HSC功能有关 以及其功能障碍如何导致骨髓衰竭和恶性肿瘤。我的初步数据表明 小鼠胚胎中DCAF7的删除导致出生的小鼠数量明显降低，而DCAF7的损失 在成年小鼠中，HSC自我更新和分化。那是我的假设是DCAF7是必不可少的 通过调节蛋白抑制剂和分化基因的表达来调节造血的调节剂。我提出的 研究将通过两个具体目的研究DCAF7在造血症中的作用：1）确定DCAF7的作用 损失影响胎儿和成人环境中的HSC功能，2）研究分子机制 DCAF7调节HSC功能。最终，我的研究将提供对生理学的基本见解 DCAF7的功能和调节造血的新分子机制的发现。这项研究 在Crispino博士的指导下，将在圣裘德儿童研究医院完成 该领域的专家委员会。这个K01职业发展奖对于扩大我的职业和 制定造血基础科学研究计划。这将使我能够实现我的研究目标 并成功过渡以建立我自己的研究小组。此外，它将为我提供 有机会由干细胞生物学，表观遗传学和泛素化的主要专家团队召集。作为 我的一部分培训，我还将参加活动，以增强我的领导，写作和口头表现 技能。这些概念和技术专长以及专业发展的其他领域将是 既要完成该提案，又建立经营我自己的研究小组所需的技能。