Optical probes of cardiac channel function

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DESCRIPTION (provided by applicant): Ion channels are at the heart of a number of human pathophysiological conditions. Either as channelopathies, side effects of drugs, or as a result of pathological remodeling of tissues, ion channel irregularities account for a major segment of human disease. Epilepsy, migraine, cardiac arrhythmias, cystic fibrosis, and a number of excitability diseases represent major human maladies. As such the underlying channel abnormalities are the focus of intensive drug development. However, currently there is no systematic high-throughput (or even medium throughput) method of screen compound libraries for ion channel activity. There are a number of pharmaceuticals that have been developed that alter ion channel function most have be discovered by basic scientific studies or serendipitously. This project seeks to develop a platform technology that can generate fluorescent cellular assays of ion channel function. These assays will be used in high-throughput screens of compound libraries. The reporters are developed by the random insertion of a fluorescent protein sequence within the target channel's sequence and the subsequent analysis of these insertion libraries for reporter activity. This Phase I project will establish the proof of concept by developing a library of human ether-a-go-go related gene (HERG) channel constructs and test these channels for function. Phase II will develop the commercial technology that will allow the large scale and high throughput development and screening of insertional libraries to develop probes to any number of pathophysiologically important ion channels