Neuropilin function in developmental and tumor angiogenesis

神经毡蛋白在发育和肿瘤血管生成中的功能

• 批准号: 6668225
• 负责人: MICHAEL KLAGSBRUN
• 金额: $ 9.16万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-30 至 2003-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6668225
• 关键词: SCID mouse; angiogenesis; angiogenesis factor; angiogenesis inhibitors; antisense nucleic acid; cell communication molecule; cell growth regulation; cell line; growth factor receptors; membrane proteins; metastasis; neoplasm /cancer blood supply; neoplastic growth; nonmammalian vertebrate embryology; protein isoforms; protein structure function; receptor binding; receptor expression; tissue /cell culture; vascular endothelial growth factors; zebrafish

NRP1 and NRP2 are cell surface receptors for VEGF and class 3A semaphorins. NRPs are necessary for normal vasculogenesis and angiogenesis in the developing mouse embryo. NRPs are expressed by tumor cells and bind VEGF. Inducible expression of NRP1 in tumor cells enhances tumor angiogenesis and tumor progression, possibly in a VEGF-dependent manner. On the other hand, semaphorins may be tumor antagonists. Sema3A inhibits in vitro angiogenesis, and preliminary results in prostate tumors indicate that Sema3F is absent in metastatic lesions. It is proposed to expand these studies in new directions with an emphasis on in vivo experimentation. In the first aim, developmental angiogenesis will be explored in the zebrafish, an excellent system for studying developmental processes, since embryonic development is rapid, the embryos are transparent, and 100-200 eggs are laid outside of the organism, allowing ready and statistical manipulation of the embryos, in preliminary studies, zebrafish NRP1 (zNRP) has been cloned. Antisense morpholino oligonuceotides that block zNRP1 synthesis result in cardiovascular anomalies. It is proposed to continue these functional studies and to extend them to NRP2, other VEGF family members that bind to NRPs (PIGF VEGF-B and VEGF-E), other angiogenesis factors and angiogenesis inhibitors. In the second aim the function of NRPs and semaphorins in tumors will be analyzed in vivo. Since Sema 3F is down-regulated in metastatic lesions, it will be overexpressed in highly metastatic tumor cells and analyzed for effects on tumor growth, tumor angiogenesis and metastasis. So will Sema3A. The overall goal is to delineate the function of NRPs and their ligands in developmental and tumor angiogenesis, processes which may have molecular properties in common. Our Specific Aims are: 1) To analyze the function of neuropilins and their ligands in a zebrafish model of developmental angiogenesis; 2) To analyze the function of neuropilins and semaphorins in mouse models of tumor angiogenesis and metastasis.

NRP 1和NRP 2是VEGF和3A类信号蛋白的细胞表面受体。NRP是发育中的小鼠胚胎中正常血管发生和血管生成所必需的。NRP由肿瘤细胞表达并结合VEGF。NRP 1在肿瘤细胞中的诱导表达可能以VEGF依赖的方式增强肿瘤血管生成和肿瘤进展。另一方面，脑信号蛋白可能是肿瘤拮抗剂。Sema 3A抑制体外血管生成，前列腺肿瘤中的初步结果表明，Sema 3F在转移性病变中不存在。建议在新的方向上扩展这些研究，重点是体内实验。在第一个目标中，将在斑马鱼中探索发育性血管生成，斑马鱼是研究发育过程的极好系统，自胚胎发育以来， 由于斑马鱼发育迅速，胚胎透明，在生物体外产下100-200个卵，允许对胚胎进行准备和统计操作，在初步研究中，斑马鱼NRP 1（zNRP）已经被克隆。阻断zNRP 1合成的反义吗啉寡核苷酸导致心血管异常。建议继续这些功能研究并将其扩展到NRP 2、与NRPs结合的其他VEGF家族成员（PIGF VEGF-B和VEGF-E）、其他血管生成因子和血管生成抑制剂。在第二个目标中，将在体内分析NRP和信号蛋白在肿瘤中的功能。由于Sema 3F在转移性病变中下调，因此它将在高转移性肿瘤细胞中过表达，并分析其对肿瘤生长、肿瘤血管生成和转移的影响。Sema 3A也是。总的目标是描述NRP及其配体在发育和肿瘤血管生成中的功能，这些过程可能具有共同的分子特性。 我们的具体目标是：1）分析神经纤毛蛋白及其配体在斑马鱼发育性血管生成模型中的功能; 2）分析神经纤毛蛋白和脑信号蛋白在小鼠模型中的功能 肿瘤血管生成和转移。