Elucidating the role of DCAF7 on hematopoietic stem cell maintenance

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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.