The effective genetic manipulation of pluripotent, reconstituting hematopoietic stem cells should lead to function correction of the mutant phenotype in inherited disorders of bone marrow-derived cells. The long term goal of our program is to understand and correct at the molecular level, genetic diseases affecting cells derived from pluripotent hematopoietic stem cells. We believe that to attain this goal, we must understand basic biological processes that affect stem cell behavior both in vitro and in vivo. The proposed Center membership draws from a group of well-funded investigators with diverse but complementary experience in hematopoiesis and stem cells biology, retroviral- and AV-mediated gene transfer, molecular genetics, virology, bone marrow transplantation and neonatology. The group is highly collaborative and interactive with NIH-funded projects that span basic, translational and clinical research. The cores proposed in this CCEMH submission are both more mature versions of the original cores supported by our previous Centers of Excellence in Molecular Hematology grant (Stem Cell Laboratory, Vector Production Facility and Mouse Core) and extensions of these 3 existing cores (Cell and Molecular Biology Core and Gene Therapy Working Group/Biostatistics Core) to further support hematology basic research, translational hematology trials utilizing stem cells and growth factors, and the development of gene transfer technology into translational trials. These two new cores are noteworthy, as they provide the infrastructure to rigorously perform human trials, while assessing quantitatively transgene expression and biochemical endpoints, a critical component in the evaluation of gene transfer protocols. Together the CCEMH represent a logical assembly of cores needed to continue the basic work in progress and to put in place support which we believe will be needed over the next 5 years.
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