Id proteins & neovascularization of spontaneous tumors

Id蛋白

• 批准号: 7038968
• 负责人: ROBERT I BENEZRA
• 金额: $ 49.18万
• 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 2009-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7038968
• 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已被证明对于小鼠皮下肿瘤的新血管化至关重要。 这些蛋白质抑制基本螺旋环螺旋转录因子的活性，通过基因靶向实验表明，对于骨髓（BM）中循环内皮细胞前体（CEP）的扩展至关重要，并且它们的动员在响应VEGF的血浆水平的响应中响应于外围。 因此，ID基因敲除小鼠在对成年动物中严重的抗血管生成应激的影响进行建模很有用。 当前的建议旨在以几种重要的方式扩展这些观察结果。 首先，我们将确定BM衍生的CEPS是否具有自发性鼠肿瘤，因为这些模型在生理上与人类疾病更加相关。 这种贡献的功能意义也将通过用明显的野生型BM移植ID基因敲除动物来测试。 此外，我们将确定BM衍生的lin-干细胞中的ID丢失是否足以赋予ID敲除表型，以便正式证明BM衍生血管细胞中ID的需求。 最后，我们将识别ID目标基因，这些基因在响应VEGF的ID敲除动物的BM中被误导。 这些研究将进一步了解ID蛋白在产后血管生成中的作用以及更普遍的自发肿瘤中新血管生成的分子机制。