Redefining the Hematopoietic Microenvironment
Final rept. 30 Sep 2011-29 Mar 2013
FRED HUTCHINSON CANCER RESEARCH CENTER SEATTLE WA
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Hematopoietic stem cells HSC and their progeny reside in specialized niches of the microenvironment ME in the bone marrow. The ME niches control HSC self-renewal, differentiation, and maturation. The ME niche cells are derived from non-hematopoietic cells, including fibroblasts, osteoblastic and endothelial cells. Macrophages, which are hematopoietic in origin, are also a critical component of the ME niches, and can influence the function of the ME niche cells. I hypothesize that the macrophages can acquire defects that may compromise ME function and lead to bone marrow failure. To test this hypothesis, I proposed to develop a new in vivo model that allows the inducible depletion of the macrophages in dogs, followed by the documentation of marrow failure, and subsequent therapeutic interventions. At this period, I achieved 4 goals 1 Optimize culture conditions for generating dog macrophages, 2 Optimize transduction efficiency of a macrophage-specific CD163 promoter construct in dog CD34 HSC and test its macrophage-specific expression, 3 Establish a luciferase reporter assay to test the macrophage-specific promoter activity, and 4 Generate multiple lentiviral vectors containing the doghuman CD163 promoter, iCasp9, and p140MGMT constructs.
- Anatomy and Physiology
- Medicine and Medical Research