(Taken directly from the application) The central hypothesis of our research is that the loss of CFTR-mediated, apical membrane chloride conductance is the fundamental physiological defect that leads to airways disease in cystic fibrosis. The general goal of our research is to confirm or negate that hypothesis. The most puzzling aspect of CF lung disease is how it begins. A direct attack on that question is not possible at present because no adequate animal model of human CF lung disease exists. Elsewhere, we propose a strategy to produce such a model. Here, we propose experiments that are feasible with available model tissues and that deal with two of most basic questions in CF research: how does CFTR operate as an ion channel, and what other chloride ion channels are important players in the lung. The proposal has 4 specific aims.
Aim 1 is to understand the mechanism and functional significance of natural """"""""lock-open"""""""" kinetics that we have discovered in CFTR channels of human airway cells.
Aim 2 is to test the hypothesis that some mutations in CFTR lead to disease in whole or in part because they interfere with CFTR's ability to display locked-open kinetics.
Aim 3 is to identify other chloride channels and determine their role in airway cell function.
Aim 4 is to study changes in channel populations that occur with epithelial cell polarization.
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