This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Cystic fibrosis is one of the most common inherited disorders, afflicting approximately 1 in 3000 newborn. The primary cause of cystic fibrosis is a phenylalanine deletion in the CFTR chloride channel at position 508, which is designated deltaF508 CFTR: individuals homozygous for this mutation develop severe lung inflammation and typically have a shortened life-span. DeltaF508 CFTR is trafficking deficient; it fails to reach the cell surface, and appears to accumulate in intracellular compartments where it undergoes degradation or forms aggregates. The mechanistic basis for the trafficking deficiency is largely unknown. We would like to trace the progression of wild type and mutant CFTR in the secretory pathway using cells that are deficient in components of the cellular quality control machinery. Methods to express CFTR in cells deficient in ubiquitinylation, COP I complex formation and cellular sorting are available to examine the pathway of trafficking. The Flash technique may provide a useful tool to trace CFTR in these cells to elucidate the mechanistic basis of the trafficking deficiency.
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