Id proteins & neovascularization of spontaneous tumors

Id蛋白

• 批准号: 7215739
• 负责人: ROBERT I BENEZRA
• 金额: $ 52.03万
• 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/7215739
• 关键词: Angioblast; BHLH Protein; Bone Marrow; Bone Marrow Stem Cell; Defect; Endothelial Cells; Gene Expression; Gene Targeting; Genes; Knock-out; Knockout Mice; Mediating; Modeling; Molecular; Mus; Peripheral; Phenocopy; Phenotype; Plasma; Proteins; RNA Interference; Research Personnel; Role; Stem cells; Stress; Testing; Transplantation; Vascular Endothelial Growth Factors; Vascularization; angiogenesis; design; helix-loop-helix protein differentiation inhibitor; human disease; in vivo; knockout animal; mature animal; neovascularization; postnatal; precursor cell; research study; response; subcutaneous; tumor

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形成是必需的。 这些蛋白质可抑制碱性螺旋环螺旋转录因子的活性，基因靶向实验已表明，它们对于骨髓 (BM) 中循环内皮细胞前体 (CEP) 的扩增以及响应血浆 VEGF 水平升高而动员至外周至关重要。 因此，Id 基因敲除小鼠可用于模拟成年动物严重抗血管生成应激的影响。 当前的提案旨在以几个重要的方式扩展这些观察结果。 首先，我们将确定 BM 衍生的 CEP 是否使自发性小鼠肿瘤血管化，因为此类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具有标记野生型BM的Id敲除动物来测试。 此外，我们将确定 BM 来源的林干细胞中的 Id 丢失是否足以赋予 Id 敲除表型，以便正式证明 BM 来源的成血管细胞对 Id 的需求。 最后，我们将鉴定 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，更广泛地理解自发性肿瘤中新血管生成的分子机制。