Epidermal growth factor (EGF)/transforming growth factor alpha (TGFalpha) is one of the most widely distributed families of growth factors in the body. They are potent mitogens and angiogenic factors that have been implicated to promote tumor growth and wound healing. Interleukin 1 alpha and beta (IL-1) are ubiquitous cytokines that mediate inflammation as well as normal or abnormal cell growth and development. The primary goals of this project are two fold. First, the proposed research will develop cell- type antagonists of these two growth factor families for the therapeutic intervention. The EGFs and IL-1 are particularly suitable targets since they may share similar principles in the design of their antagonist. Second, they are aimed to expand the peptide chemistry for the rational design of growth factors and to use these antagonists for biochemical studies. These will include the chemical goals of developing the domain ligation strategy and defining approaches for the design of antagonist, as, well as the biological goal of applying growth factor antagonists to study the cellular signal transduction mechanism that will aid the rational design of growth factor antagonists. In general, the goals of this project will be built upon the progress and leads made during the present period.
The specific aims are as follows: 1. Design and synthesis of antagonists of EGF/TGFalpha and IL1. 2. Develop domain ligation strategy for the synthesis of growth factor antagonists and mosaic proteins. 3. Develop mosaic growth factors that confer cell type selectivity. 4. Determine the structures of selected growth factor antagonists by 2D NMR. 5. Use EGF antagonists to study endogenous substrates and to identify the signal transduction mechanism of EGF receptor and to help the rational design of EGF antagonists. 6. Study of in vivo efficacy of EGF antagonists in nude mice.
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