This is a revised version of competitive renewal NIH RO1 HL67384. During this grant, we uncovered a number of intracellular signaling molecules activated by Stromal Cell Derived Factor-1 (SDF-1/CXCL12), and mediated through its receptor, CXCR4, for survival enhancing effects on Hematopoietic Progenitor Cells (HPC). We began an evaluation of SDF-1/CXCL12 survival enhancing/anti-apoptosis effects on murine competitive repopulating hematopoietic stem cells (HSC), and on murine embryonic stem (ES) cell lines. Our studies will now focus mainly on SDF-1/CXCL12 and CXCR4 effects on survival/anti-apoptosis and self-renewal of murine HSC and ES cells under conditions of differing oxygen tension. Our overall hypothesis is that SDF-1/CXCL12 is involved in survival and self-renewal of murine HSC and ES cells and that these effects are mediated by a variety of interacting intracellular signals, a number of which regulate the cell cycle. Moreover, lowered oxygen tension has been shown by us and others to regulate the response of HPC to growth modulatory cytokines and by others to influence HSC proliferation and self-renewal, which makes it important to evaluate effects of lowered oxygen tension within studies which assess effects of growth regulatory cytokines on immature blood cell compartments.
The Specific Aims are to: 1) Determine actions of SDF-1/CXCL12 on survival/anti-apoptosis and self-renewal of long-term marrow competitive and noncompetitive adult murine bone marrow repopulating HSC at normoxia and in a 1% hypoxic environment. 2) Determine mechanistic roles of Mad2, p21cip1/waf1 and Stat3 first, and also BCL-6, BAZF, and Sirtl and 1% hypoxia on SDF-1/CXCL12 survival enhancing effects for murine bone marrow HSC and HPC. 3) Clarify roles of SDF-1/CXCL12, and its receptor CXCR4, on survival and self-renewal of murine ES cells, under hypoxic and normoxic conditions. It is our belief that by evaluating factors that modulate the survival and self renewal of both murine adult HSC and ES cells, information learned with one cell type will be of value to understanding functions of the other cell type. These studies should enhance our knowledge of factors enhancing survival and self-renewal of stem cells, information that may be of clinical utility. ? ? ?
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