Id proteins & neovascularization of spontaneous tumors

Id蛋白

• 批准号: 6764661
• 负责人: ROBERT I BENEZRA
• 金额: $ 47.5万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-04-01 至 2009-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6764661
• 关键词: DNA binding protein; RNA interference; angiogenesis; bone marrow; cell cycle; disease /disorder model; genetic regulation; genetically modified animals; inhibitor /antagonist; laboratory mouse; microarray technology; neoplasm /cancer blood supply; neoplastic growth; protein structure function; stem cells; transcription factor; transfection /expression vector; vascular endothelial growth factors

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.

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至关重要。这些蛋白抑制基本螺旋环螺旋转录因子的活性，基因靶向实验表明，这些蛋白对于骨髓（BM）中循环内皮细胞前体（cep）的扩张以及它们在血浆VEGF水平升高时向外周的动员至关重要。因此，Id敲除小鼠在模拟成年动物严重抗血管生成应激的影响方面是有用的。目前的建议旨在从几个重要方面扩展这些观察结果。首先，我们将确定BM衍生的cep是否会使自发性小鼠肿瘤血管化，因为这种模型在生理上与人类疾病更相关。这种贡献的功能意义也将通过移植带有标记野生型BM的Id敲除动物来测试。此外，为了正式证明BM来源的成血管细胞对Id的需求，我们将确定BM来源的lin- stem细胞中的Id缺失是否足以赋予Id敲除表型。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VEGF而被错误调控。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，并更广泛地了解自发性肿瘤中新生血管生成的分子机制。