ANALYSIS OF Id GENE TARGETS IN TUMOR ENDOTHELIAL CELLS

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DESCRIPTION (provided by applicant): Angiogenesis-the formation of new blood vessels is critical for tumor growth and metastasis. Elucidating the precise molecular mechanisms of angiogenic regulation is key to designing rational anti-angiogenic therapeutic strategies and is an area of intense investigation. In the past decade, several molecules regulating critical angiogenic pathways were identified, yet the molecular basis of blood-vessel formation in tumors, is still incompletely understood. It is clear, however that some of the key players in angiogenesis are the helix-loop-helix Id proteins. The major goal of our research is to elucidate the molecular mechanisms involved in the complex process of neoangiogenesis in tumors. In adult mice, transcription factors Id1 and Id3 are over expressed in the endothelium of the blood vessels of tumors but not in the resting vessels. Loss of Id1 and Id3 causes severe defects in tumor-induced neovascularization and impairs growth and metastasis of both xenografts and physiologically relevant spontaneous tumors. The Id mouse model is therefore useful to study postnatal neoangiogenesis relevant to tumors. Our broad specific aims are to identify Id regulated genes in the endothelial cells of tumors, determine their functional role in promoting cell proliferation, cell migration, ultimately tumor neovascularization. The identification and functional analysis of Id transcriptional targets will not only provide fundamental insights into the role of Id as a transcription modulator, but also impact development of rational anti-angiogenic therapeutic interventions that disrupt Id-mediated tumor growth in human.