Cystic fibrosis (CF) is a common lethal autosomal recessive genetic disease in the Caucasian population affecting some 30,000 people in the European Union and more than 100,000 in the world. The disease is caused by the mutation of a gene coding for a memb rane protein, the cystic fibrosis transmembrane conductance regulator (CFTR), an epithelial anion channel with complex regulation. Knowledge and understanding of CFTR malfunction in CF is leading to rational new approaches to therapy for CF patients. Bypa ssing CFTR dysfunction using artificial chloride transporters is one such possibility. However, suitable transport systems have been unavailable until very recently. The proposed project involves the design and construction of synthetic anion channels (o rganic synthesis, supramolecular chemistry), and the study of their anion transport properties using electrophysiological techniques (patch clamp, Ussing chamber etc.). The design will employ a steroid-based architecture, related to a family of receptors which have previously been shown to act as anion carriers. By changing from a carrier to a channel mechanism, far higher activities are expected. The selectivity associated with the steroid-based structure should, however, be retained. The research will take place in two Departments of the University of Bristol: the School of Chemistry and the Department of Physiology. The applicant will thus belong to two groups and will receive a broad range of experience and training. In particular, the project will enhance the applicant's skills in synthetic chemistry, and will also provide a training in electrophysiological methods. Through this experience, and through complementary training, he will be well-positioned for a future independent scientific career at the chemistry-biology interface. The research will throw light on the mechanism of anion permeation through natural chloride channels, and might ultimately lead to treatments for CF and related diseases.
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