This proposal establishes a five year plan for Dr. William Slayton to develop the skills and experience needed to be a successful clinician/scientist in the field of Pediatric Hematology/Oncology. Currently, Dr. Slayton has completed 1 year of clinical fellowship and 2.5 years of mentored research. Dr. Slayton has a strong interest in developmental hematopoiesis, and completed 15 months in the lab of Dr. Robert Christensen, defining the role of cytokines in neutrophil and macrophage development in the human fetus. He relocated to Salt Lake City to work in the laboratory of Dr. Gerald Spangrude, where he has spent the last 11 months devising techniques to isolate megakaryocyte progenitors from mouse bone marrow. Dr. Slayton's immediate goal is to broaden his research skills through a combination of a carefully structured didactic teaching program and completion of a research project in the laboratory of his mentor. Dr. Slayton's long-term career goal is to become an independent investigator capable of combining the discipline of developmental hematology with issues in clinical hematology, leukemogenesis, and bone marrow transplantation. Dr. Slayton's research project is based on the hypothesis that the megakaryocytic and erythroid lineages separate from the myeloid and lymphoid lineages early in the hematopoietic hierarchy. This hypothesis is based on the observations in the Spangrude laboratory of a progenitor population that reconstitutes lymphoid and macrophage lineages, but fails to reconstitute erythrocytic and megakaryocytic lineages, and is supported by the behavior of progenitors in the fetal liver, several knockout models, and several tumor cell lines. The Spangrude lab has established all of the assays necessary for this study. Enriched populations of multipotent progenitor cells will be isolated using a cell sorter based on expression of cell surface markers and mitochondrial stains. Cell behavior will be defined in vitro through tissue culture studies, and in vivo through transplantation experiments. Finally, these enriched populations will be used to produce cDNA libraries, which will be used to study the expression of genes known to be involved in hematopoietic commitment, as well as used in differential expression and microarray assays to look for the expression of novel genes. Dr. Spangrude's laboratory provides an excellent environment for Dr. Slayton to carry out this proposal. A research advisory committee that meets the NIH requirements has been guiding Dr. Slayton's research progress. In this rich and supportive environment, Dr. Slayton will gain the experience necessary to contribute to the understanding of the early cellular and molecular events in megakaryopoiesis.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Clinical Investigator Award (CIA) (K08)
Project #
1K08HL003962-01A1
Application #
2907103
Study Section
Special Emphasis Panel (ZHL1-CSR-K (M1))
Project Start
1999-09-15
Project End
2004-08-31
Budget Start
1999-09-15
Budget End
2000-08-31
Support Year
1
Fiscal Year
1999
Total Cost
Indirect Cost
Name
University of Utah
Department
Pediatrics
Type
Schools of Medicine
DUNS #
City
Salt Lake City
State
UT
Country
United States
Zip Code
84112
Li, Xiao-Miao; Hu, Zhongbo; Jorgenson, Marda L et al. (2009) High levels of acetylated low-density lipoprotein uptake and low tyrosine kinase with immunoglobulin and epidermal growth factor homology domains-2 (Tie2) promoter activity distinguish sinusoids from other vessel types in murine bone marrow. Circulation 120:1910-8
Slayton, William B; Li, Xiao-Miao; Butler, Jason et al. (2007) The role of the donor in the repair of the marrow vascular niche following hematopoietic stem cell transplant. Stem Cells 25:2945-55
Ignatz, Mark; Sola-Visner, Martha; Rimsza, Lisa M et al. (2007) Umbilical cord blood produces small megakaryocytes after transplantation. Biol Blood Marrow Transplant 13:145-50
Slayton, William B; Wainman, David A; Li, Xiao Miao et al. (2005) Developmental differences in megakaryocyte maturation are determined by the microenvironment. Stem Cells 23:1400-8
Fisher, Robert C; Slayton, William B; Chien, Christopher et al. (2004) PU.1 supports proliferation of immature erythroid progenitors. Leuk Res 28:83-9
Meeker, Nathan D; Goldsby, Robert; Terrill, Kelly R et al. (2003) Dapsone therapy for children with immune thrombocytopenic purpura. J Pediatr Hematol Oncol 25:173-5
Holt, Derick; Brown, Justin; Terrill, Kelly et al. (2003) Response to intravenous immunoglobulin predicts splenectomy response in children with immune thrombocytopenic purpura. Pediatrics 111:87-90
Spangrude, Gerald J; Perry, S Scott; Slayton, William B (2003) Early stages of hematopoietic differentiation. Ann N Y Acad Sci 996:186-94
Slayton, William B; Spangrude, Gerald J; Chen, Zhong et al. (2002) Lineage-specific trisomy 21 in a neonate with resolving transient myeloproliferative syndrome. J Pediatr Hematol Oncol 24:224-6
White, C; Chen, Z; Raetz, E et al. (2002) Using fluorescence-activated cell sorting followed by fluorescence in situ hybridization to study lineage relationships: the 8;21 translocation is present in neutrophils but not monocytes in a patient with severe congenital neutropenia and a granulocyte c Acta Paediatr Suppl 91:120-3

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