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.
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