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Elucidating the role of DCAF7 on hematopoietic stem cell maintenance

阐明 DCAF7 对造血干细胞维持的作用

基本信息

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
项目类别：
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&apos 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

项目摘要

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.

项目总结