Hematopoietic stem cells comprise a very small fraction of bone marrow mononuclear cells, which retain the capacity for self-renewal as well as controlled differentiation into all the cellular elements of the peripheral blood. The molecular signals that confer the stem cell phenotype and the mechanisms that control stem cell proliferation and differentiation are incompletely understood. In preliminary work, we have identify a divergent homeobox gene (Pitx2) that is expressed in murine hematopoietic stem/progenitor cells but not in differentiated cells. Our studies have demonstrated the expression of a novel mRNA isoforms of this gene in hematopoietic stem/progenitor cells and embryonic stem cells. The research goals of this proposal are to establish the role of this gene in hematopoiesis. Specifically, we propose to: characterize the temporal and over-expression of the gene (products) on hematopoietic progenitor cell growth and differentiation in vitro as well as in vivo: study the effects of loss of function of the gene in ES cells carrying targeted disruptions of the gene as well as in various hematopoietic cells expressing a dominant negative version of Pitx2; and characterize the downstream gene targets of Pitx2 as well as the elements that regulate the expression of Pitx2.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL063357-04
Application #
6647335
Study Section
Project Start
2002-08-01
Project End
2003-07-31
Budget Start
Budget End
Support Year
4
Fiscal Year
2002
Total Cost
Indirect Cost
Name
Yale University
Department
Type
DUNS #
082359691
City
New Haven
State
CT
Country
United States
Zip Code
06520
Wilson, Michael; Tsakraklides, Vasiliki; Tran, Minh et al. (2016) EVI1 Interferes with Myeloid Maturation via Transcriptional Repression of Cebpa, via Binding to Two Far Downstream Regulatory Elements. J Biol Chem 291:13591-607
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Khanna-Gupta, Arati; Abayasekara, Nirmalee; Levine, Michelle et al. (2012) Up-regulation of translation eukaryotic initiation factor 4E in nucleophosmin 1 haploinsufficient cells results in changes in CCAAT enhancer-binding protein ? activity: implications in myelodysplastic syndrome and acute myeloid leukemia. J Biol Chem 287:32728-37
Khanna-Gupta, Arati (2011) Regulation and deregulation of mRNA translation during myeloid maturation. Exp Hematol 39:133-41
Halene, Stephanie; Gao, Yuan; Hahn, Katherine et al. (2010) Serum response factor is an essential transcription factor in megakaryocytic maturation. Blood 116:1942-50
Lee, Han M; Zhang, Hui; Schulz, Vincent et al. (2010) Downstream targets of HOXB4 in a cell line model of primitive hematopoietic progenitor cells. Blood 116:720-30
Halene, Stephanie; Gaines, Peter; Sun, Hong et al. (2010) C/EBPepsilon directs granulocytic-vs-monocytic lineage determination and confers chemotactic function via Hlx. Exp Hematol 38:90-103
Rabinovich, Peter M; Komarovskaya, Marina E; Wrzesinski, Stephen H et al. (2009) Chimeric receptor mRNA transfection as a tool to generate antineoplastic lymphocytes. Hum Gene Ther 20:51-61
Cheng, Ee-Chun; Luo, Qing; Bruscia, Emanuela M et al. (2009) Role for MKL1 in megakaryocytic maturation. Blood 113:2826-34
Friedman, Rachel S C; Krause, Diane S (2009) Regeneration and repair: new findings in stem cell research and aging. Ann N Y Acad Sci 1172:88-94

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