Cystic fibrosis (CF) is a fatal disease caused by loss of function of an ion channel, the cystic fibrosis transmembrane regulator (CFTR). Loss of the beta-adrenergic response has long been used in the diagnosis of CF, however the role of this pathway in the pathophysiology of the disease is unknown. Thebeta adrenergic receptor is coupled to Gs-alpha and leads to activation of adenylyl cyclase. To evaluate the role of G-protein signaling in CFTR activation, patients with known heterozygous mutations in the gene encoding Gs-alpha, GNAS1, will be studied. This project will seek to answer the following questions: 1) Is RNA transcript equally expressed from the GNAS1 genes in nasal epithelium? 2) What is the level of Gprotein signaling in the nasal epithelium of AHO patients? 3) Does a reduction in G-protein signaling lead to impaired CFTR function? A quantitative assay of expression of maternal and paternal alleles of GNAS1 will be performed on patient-derived nasal epithelial RNA based on RT-PCR and capillary electrophoresis of transcripts with known polymorphisms. Cyclic AMP assays, RNA expression levels, and 3 clinical tests of CFTR function will be evaluated on nasal epithelia from patients.
| Hsu, Stephanie C; Groman, Joshua D; Merlo, Christian A et al. (2007) Patients with mutations in Gsalpha have reduced activation of a downstream target in epithelial tissues due to haploinsufficiency. J Clin Endocrinol Metab 92:3941-8 |
