The University of Wisconsin Bioengineering Research Partnership (UW-BRP) will focus on the development of new molecular analysis tools that possess the potential to be used to identify and validate biological endpoints whereby the activity of novel anti-cancer agents can be more accurately and rapidly evaluated as to their molecular mechanism(s) and clinical relevance. The work will initially be focused on the analysis of the epidermal growth factor receptor (EGFR), given that its over expression and mutation has been well-associated with some of the most incurable cancers. However, it is anticipated that the principles to be developed will be sufficiently versatile to be applied to other key signaling molecules in the future. Whereas the basis of existing high throughput screens largely restricts their application to in vitro molecular analyses of enriched preparations of receptors or other signaling molecules, the UW-BRP seeks to establish principles for tools that can also be applied to the analysis of samples from cultured cells and from biopsies of xenographs and spontaneous tumor tissues. This capability will ultimately enable a fundamental approach that will span the molecular, cellular and tissue levels and will be used in both basic research and in animal and human clinical trials. In the present proposal, a multidisciplinary team of researchers with diverse expertise in chemical and biological engineering, chemistry and biochemistry, and the biomolecular and biomedical sciences proposes to develop a broadly-applicable bioanalytical approach that integrates advances in the following areas: a) the nano-fabrication of surfaces, b) the development of synthetic and biochemical strategies for the covalent and oriented immobilization of proteins and peptides on surfaces, c) the implementation of liquid crystals as highly sensitive reporters of the presence of proteins captured on surfaces, and d) the investigation of key cell signaling proteins that participate in processes associated with carcinogenesis. Specifically, the analytical characteristics of liquid crystals for reporting the behavior of the well-recognized anti-cancer target, i.e. the EGF receptor, will be compared to conventional analytical methods in a study that will a) rapidly and sensitively assess the levels and activity of wild-type and mutant human EGF receptor in biological samples, b) test the hypothesis that wild-type and oncogenic forms of the EGF receptor exhibit differential inhibitor specificity, and c) assess if agents that potently inhibit EGF-mediated events in vitro will also exhibit a capacity to antagonize EGF receptor expression and/or activity in cell culture. These studies will use the EGF receptor system as a prototype and it is anticipated that the technology will be readily adaptable to a wide range of other molecular targets. In the long term, these new tools should be useful for the assessment of the molecular mechanisms and consequences of anti-cancer agents, thereby facilitating their research from basic biology through to clinical assessment of efficacy.
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