Id proteins & neovascularization of spontaneous tumors

描述(由申请人提供)：ID蛋白ID1和ID3已被证明对小鼠皮下肿瘤的新生血管是必不可少的。基因打靶实验表明，这些蛋白抑制碱性螺旋环螺旋转录因子的活性，对于骨髓循环内皮细胞前体(CEPs)的扩增以及它们在血浆VEGF水平升高时向外周动员是必不可少的。因此，ID基因敲除小鼠在模拟严重抗血管生成应激对成年动物的影响方面是有用的。目前的提议旨在以几种重要方式扩大这些观察结果。首先，我们将确定BM来源的CEPs是否使自发的小鼠肿瘤血管化，因为这样的模型在生理上与人类疾病更相关。这一贡献的功能意义也将通过移植带有标记的野生型BM的ID基因敲除动物来测试。此外，我们将确定骨髓来源的LIN干细胞中的ID缺失是否足以赋予ID基因敲除表型，以便正式证明BM来源的血管母细胞对ID的需求。最后，我们将确定ID靶基因，这些基因在ID基因敲除动物的骨髓中被错误调控，以响应血管内皮生长因子。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，更广泛地理解自发肿瘤中新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.