Blood cells of multiple lineages (red cells, neutrophils, monocyte/macrophages, mast cells, B-lymphoid and T-lymphoid cells) are produced from rare hematopoietic stem and progenitor cells. Hematopoietic stem cells are defined as cells that have the ability to regenerate themselves (self-renewal) and to give rise to mature cells of a particular lineage through differentiation. Understanding the mechanisms that regulate stem cell self-renewal and differentiation is the most important issues in this area since it promise fundamental insight not only into the origin and design of multicellular organisms but also into blood cancer biology. Our major efforts are focused on identification and functional characterization of regulatory molecules (small GTPases and nuclear transcriptional factors) that are important for the self-renewal and differentiation of hematopoietic stem and progenitor cells. Another area we are investigating is retroviral-mediated gene transfer into hematopoietic stem and progenitor cells. Gene therapy using human hematopoietic stem and progenitor cells has great potential as an approach to genetic and acquired diseases affecting blood cells and immune systems because hematopoietic stem cells can completely and permanently replace the host hematopoietic and immune systems after bone marrow transplantation. Retroviral vectors are able to introduce genes stably and safely into many types of cells, including primitive hematopoietic cells, through integrating efficiently into the target cell genome. Therefore retroviral vectors have been the primary tool for hematopoietic stem/progenitor cell gene transfer, since integration into the host genome is absolutely required in order to pass on the transgene to progeny cells. In collaboration with Dr. Hal Broxmeyer, we are working with various ways to improve the efficiency of retroviral transduction into hematopoietic stem and progenitor cells as well as the engraftment of the transduced cells. Ultimately, we hope to achieve reproducible gene transfer to levels that would be adequate for many therapeutic applications.
