) There is a growing number of diseases characterized by the uncontrolled growth of new capillaries. These are now considered to be """"""""angiogenic diseases"""""""". These diseases include solid tumor growth and metastases, rheumatoid arthritis and many others. The availability of a drug which could prevent the spread of vascularization would have broad applicability as a therapy for these diseases. Cartilage has been studied as a potential source of an angiogenesis inhibitor(s) because of its avascularity and its tumor-resistance. The use of cartilage as a potential source of angiogenesis inhibitor is not limited to mammalian sources. For example, we have demonstrated the presence of angiogenesis inhibitors in shark cartilage, however this factor(s) has yet to be purified or identified. In this application, we propose to bring our experience in the purification and characterization of cartilage-derived angiogenesis inhibitors to the study of shark cartilage as a source of anti- angiogenic factors in the context of the following Specific Aims: (1) Purification of a shark cartilage-derived inhibitor(s) of angiogenesis. Using a purification strategy based on size exclusion, ion exchange, RP-HPLC, and mass spectrometry, we will purify anti-angiogenic factors from shark cartilage using an in vitro angiogenesis inhibitor assay. (2) Determination of the anti-angiogenic activity of the shark carti1age- derived inhibitor in vitro. We have developed and utilized a number of angiogenesis assays that will be used to study the samples obtained in the course of the purification protocol. These state-of-the-art assays are based on the use of capillary endothelial cells and the some of the processes that these cells undergo during successful neovascularization, such as growth factor-stimulated proliferation and migration. (3) Determination of the anti-angiogenic activity of purified shark inhibitor in vivo. After screening in the in vitro assays mentioned above, potential anti-angiogenic activity from shark cartilage will be assayed in vivo using the chick chonoallantoic assay and the rabbit corneal pocket assay.
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