Id proteins & neovascularization of spontaneous tumors

描述（由申请人提供）：已显示Id蛋白Id1和Id3对于小鼠皮下肿瘤的新血管形成是必需的。 这些抑制碱性螺旋环螺旋转录因子活性的蛋白质已通过基因靶向实验显示对于骨髓（BM）中循环内皮细胞前体（CEP）的扩增及其响应于VEGF的血浆水平升高而动员到外周中是必需的。 因此，Id敲除小鼠可用于模拟成年动物中严重抗血管生成应激的作用。 目前的建议旨在以几种重要方式扩大这些观察。 首先，我们将确定BM衍生的CEP是否使自发性鼠肿瘤血管化，因为这样的模型与人类疾病在生理学上更相关。 还将通过移植具有标记的野生型BM的Id敲除动物来测试这种贡献的功能意义。 此外，我们将确定BM来源的干细胞中的Id损失是否足以赋予Id敲除表型，以正式证明BM来源的成血管细胞中对Id的需求。 最后，我们将确定Id靶基因，这些基因在Id敲除动物的BM中响应于VEGF而被错误调节。 这些研究将进一步加深我们对Id蛋白在出生后血管生成中的作用的理解，并更普遍地了解自发性肿瘤中新生血管生成的分子机制。

DESCRIPTION (provided by applicant): 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.