The Id proteins Id1 and Id3 have been shown to be essential for neovascularization of subcutaneous tumors in mice. These proteins, which inhibit the activity of basic helix loop helix transcription factors, have been shown by gene targeting experiments to be essential for the expansion of circulating endothelial cell precursors (CEPs) in the bone marrow (BM) and their mobilization into the periphery in response to elevated plasma levels of VEGF. The Id knockout mice have therefore been useful in modeling the effects of severe anti-angiogenic stress in adult animals. The current proposal is designed to expand these observations in several important ways. First, we will determine if BM derived CEPs vascularize spontaneous murine tumors since such models are much more physiologically relevant to human disease. The functional significance of such a contribution will also be tested by transplanting Id knockout animals with marked wild type BM. In addition, we will determine if Id loss in BM derived lin- stem cells is sufficient to confer the Id knockout phenotype in order to formally demonstrate the requirement for Id in BM derived angioblasts. Finally, we will identify Id target genes, which are misregulated in the BM of Id knockout animals in response to VEGF. These studies will further our understanding of the role of Id proteins in postnatal angiogenesis and more generally the molecular mechanisms of neoangiogenesis in spontaneous tumors.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA107429-01
Application #
6764661
Study Section
Special Emphasis Panel (ZRG1-TME (01))
Program Officer
Mohla, Suresh
Project Start
2004-04-01
Project End
2009-03-31
Budget Start
2004-04-01
Budget End
2005-03-31
Support Year
1
Fiscal Year
2004
Total Cost
$475,002
Indirect Cost
Name
Sloan-Kettering Institute for Cancer Research
Department
Type
DUNS #
064931884
City
New York
State
NY
Country
United States
Zip Code
10065
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Nam, Hyung-song; Benezra, Robert (2009) High levels of Id1 expression define B1 type adult neural stem cells. Cell Stem Cell 5:515-26
Jankovic, Vladimir; Ciarrocchi, Alessia; Boccuni, Piernicola et al. (2007) Id1 restrains myeloid commitment, maintaining the self-renewal capacity of hematopoietic stem cells. Proc Natl Acad Sci U S A 104:1260-5
Shaked, Yuval; Ciarrocchi, Alessia; Franco, Marcela et al. (2006) Therapy-induced acute recruitment of circulating endothelial progenitor cells to tumors. Science 313:1785-7
Fraidenraich, Diego; Stillwell, Elizabeth; Romero, Elizabeth et al. (2004) Rescue of cardiac defects in id knockout embryos by injection of embryonic stem cells. Science 306:247-52