Hematopoietic stem cells (HSCs) play crucial roles in maintaining mature, functional cells in various tissues and provide life-saving treatments for multiple hematological disorders. Identifying the genetic factors that govern HSC number/function could thus have important therapeutic implications as well as increase our biological knowledge of this vital regenerative tissue system. In recent years, the power of genome-wide association studies (GWAS) has been overwhelmingly demonstrated in humans where hundreds of novel susceptibility alleles have been identified for a variety of clinical traits. However, human GWAS are primarily applicable to traits that can be obtained in large numbers of subjects, thus limiting the utility of this approach for other biomedically relevant phenotypes, including HSCs. To address this limitation, we will utilize the newly developed Hybrid Mouse Diversity Panel (HMDP) for GWAS in mice. In preliminary studies with ~100 HMDP mouse strains, we have identified over 10 chromosomal regions influencing HSCs. We now propose to confirm and expand these findings. In Aim 1, we will carry out in depth studies to functionally characterize two novel HSC candidate genes identified by this approach. In Aim 2, we will phenotype the remaining HMDP strains to identify additional loci associated with HSCs. These efforts could offer extensive new insight into the biological pathways controlling HSCs as well as provide targets for therapeutic development.
Statement of Benefit to California:
California is home to over 38 million people and one of the most ethnically diverse states in the country. In 2012, over 17,000 bone marrow transplants were performed in the United States, of which 20% were done in California alone. While hematopoietic stem cells (HSCs) provide life-saving treatments, fewer individuals are able to find suitable donors in California than in less ethnically diverse regions due to biases in the unrelated bone marrow donor registries. One approach for addressing these limitations is to expand the number of HSCs prior to transplantation by either manipulating them in the laboratory or increasing the numbers collected from donors. However efficient methods to implement these procedures have yet to be established. Our overall goals are to carry out a genetics study and identify the genes that control HSC number and/or function. These genes could then serve as targets for therapeutic development in order to increase the yield of HSCs for clinical treatments. This strategy could also serve as a paradigm for studying other types of stem cells.