Neuropilin function in developmental and tumor angiogenesis

NRP1和NRP2是VEGF和3A类信号蛋白的细胞表面受体。NRPs是发育中的小鼠胚胎正常血管生成和血管生成所必需的。NRPs由肿瘤细胞表达并结合VEGF。NRP1在肿瘤细胞中的诱导表达可能以vegf依赖的方式促进肿瘤血管生成和肿瘤进展。另一方面，信号蛋白可能是肿瘤拮抗剂。Sema3A抑制体外血管生成，在前列腺肿瘤中的初步结果表明，Sema3F在转移性病变中不存在。建议将这些研究扩展到新的方向，重点放在体内实验上。在第一个目标中，将在斑马鱼中探索发育血管生成，这是一个研究发育过程的优秀系统，从胚胎开始

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.