): The investigators hypothesize that the angiostatic factor IP-10 is an endogenous inhibitor of tumor-derived angiogenesis. In this proposal, they will test this hypothesis by characterizing the role of IP-10 in regulating overall tumor-derived angiogenic activity in an animal model of human non-small cell lung cancer (NSCLC). They will demonstrate that underexpression of IP-10 imparts increased angiogenic activity to NSCLC cell lines. Next, they will reconstitute IP-10 production in NSCLC cell lines, thus restoring the angiostatic balance, using two methods. (1) In vitro treatment of NSCLC cells with interferon gamma (IFNgamma) to induce IP-10 expression, and (2) Gene transfer technology to indirectly (IFNgamma) or directly (IP-10) augment IP-10 expression. They will then show that IFNgamma and IP-10 gene transfected cells have reduced in vitro angiogenic activity and reduced tumorigenicity in SCID mice. Finally, they will treat established NSCLC tumors in SCID mice with locally administered IFNgamma or IP-10 and show that IFNgamma inhibits tumor growth via an IP-10 dependent increase in angiostatic activity. These studies will lead to important new information about the pathogenesis of NSCLC, and enable the Principal Investigator to acquire the necessary skills to develop into an independent investigator.
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