Browsing by Subject "Cystic Fibrosis"
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Item Bicarbonate Secretion, Cystic Fibrosis and Congenital Chloride Diarrhea: Molecular Mechanisms in Ion Transport and Disease(2006-12-19) Dorwart, Michael Richard; Thomas, Philip J.Cystic Fibrosis (CF) and Congenital Chloride Diarrhea (CLD) are two genetic diseases which without treatment can be fatal. Cystic Fibrosis is a disease which disrupts normal fluid secretion in multiple organs and tissues, and is caused by mutations in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene. Congenital Chloride Diarrhea is a disease caused by mutations in the SLC26A3 gene, which cause patients to suffer from watery stool and dehydration. The proteins encoded by the CFTR and SLC26A3 genes have been demonstrated to be a chloride channel and a chloride-bicarbonate exchanger respectively. They have also been shown to reciprocally activate one another's transport activity. Understanding how these proteins transport chloride and bicarbonate across the apical membrane of epithelial cells, and how they mutually activate one another's transport activity is critical for our understanding of CF and CLD. The SLC26A3 protein is a membrane protein predicted to contain 12 transmembrane spanning alpha -helices, and a C-terminal STAS domain which is homologous to the bacterial anti-sigma factor antagonists. The STAS domain is required for proper SLC26A3 chloride-bicarbonate exchange function, and it is also required for the reciprocal activation of SLC26A3 and CFTR activities. Here we investigate the molecular interaction between the STAS domain of SLC26A3 and the R-domain of CFTR, as well as the molecular mechanism(s) by which four CLD causing mutations (delta Y526/7, I544N, I675/6ins and G702Tins) residing in the SLC26A3 STAS domain lead to disease. The STAS domain and R-domain have been demonstrated to directly bind to one another, and this interaction is modulated by phosphorylation of the R-domain. Functional, biochemical and cell biological experiments performed on wild type and mutant SLC26A3 proteins suggest that the CLD mutations cause transporter misfolding and/or mistrafficking. Biochemical and biophysical studies performed on the purified STAS domains suggest that these CLD causing mutations have differential effects on the STAS domain's structure. Our data taken together suggest that the CLD causing mutations cause disease by at least two distinct molecular mechanisms, ultimately leading to loss of functional protein at the plasma membrane.Item Bone Health Outcomes in Post-Lung Transplant Patients with Cystic Fibrosis(2023-05-01T05:00:00.000Z) Tran, Triet Vincent Minh; Maalouf, Naim M.; Jain, Raksha; Lederer, Eleanor D.BACKGROUND: Osteoporosis is a common comorbidity in patients with cystic fibrosis (CF). Although lung transplantation (LTx) improves quality of life of CF patients, there is little research examining long-term bone health outcomes following LTx in these patients. OBJECTIVE: We sought to compare long-term bone health outcomes in LTx patients with and without CF, as well as determine factors associated with adverse bone health in CF patients. METHODS: Data were collected on 59 patients who underwent LTx between 2006-2019, including 30 with CF and 29 without CF. We compared baseline characteristics, long-term bone mineral density (BMD) trends, and fracture incidence between the two patient populations, and examined factors associated with post-LTx fractures in CF patients. RESULTS: Compared with non-CF patients, patients with CF were younger, had lower body mass index, and lower baseline BMD Z-scores at the lumbar spine, femoral neck, and total hip (all p<0.001). BMD at all sites declined in both groups in the first year post-LTx. In subsequent years, CF patients exhibited better BMD recovery relative to pre-transplantation, but continued to have lower BMD post-LTx. Post-transplant fractures occurred in 30% and 34% of CF and non-CF patients, respectively. CF patients who developed fractures after LTx had significantly lower BMD and lower pre-transplantation percent predicted forced expiratory volume in one second (FEV1%). CONCLUSION: Although CF patients exhibit better BMD recovery following LTx compared to their non-CF counterparts, CF patients start with significantly lower pre-LTx BMD and experience a similarly high rate of post-LTx fractures. These findings highlight the unique contribution of the CF disease process to bone health, as well as a clear need for better prevention and treatment of osteoporosis in CF patients before and after LTx.Item Cotranslational Folding of CFTR(2013-05-31) Patrick, Anna Elizabeth; Thomas, Philip J.; Albanesi, Joseph P.; Gardner, Kevin H.; Jiang, YouxingThe life of the cystic fibrosis transmembrane conductance regulator (CFTR) protein in the cell is dictated by its biogenesis, cellular trafficking, regulated function, and destruction. Cystic fibrosis (CF) is the direct result of perturbations in these processes. Treatment of CF mandates the understanding of the molecular events leading to CFTR loss-of-function. The mechanisms by which different mutations throughout the CFTR protein result in misfolding are unclear. The correction of these processes and ultimately the treatment of CF require elucidation of these mechanisms. In this report, CF-causing mutations in the first transmembrane (TM) spanning domain (TMD1) that result in CFTR misfolding are examined. First, the G85E and G91R mutations in TM1 are shown to have different molecular pathologies. For G85E, TM1 is destabilized in the membrane by the ionizable side chain, which correlates with temperature insensitive ER accumulation. By contrast, G91R does not destabilize TM1, which correlates with temperature sensitive ER accumulation. Both mutants were then identified to perturb TMD1 in a manner recognizable by the cell. Finally, consistent with propagation of these defects, all multidomain CFTR constructs were recognized and degraded in the cell. Other mutations in the interdomain interface between TMD1 and the cytosolic nucleotide binding domains (NBDs) did not perturb TMD1, but affected multidomain constructs containing four domains, which can traffic from the ER. Notably, the interface mutants that change a hydrophobic residue to a basic residue increased levels of early multidomain constructs, suggesting a tradeoff between transient stability and later formation of interdomain interactions. The major cellular monitoring of most mutants occurs after TMD2 is present. In most current models, CF-causing mutations like ?F508 are shown to perturb interdomain interactions before TMD2 is produced. However, evidence presented here suggests these interactions are not important until after TMD2 production. The comparison of TM1 mutants and other mutants supports specific domain interactions in the hierarchical folding model. Taken together, the data herein generate a model of CFTR folding that begins with TMD1. Interdomain interactions then become important in a four domain construct, and the final domain confers additional stability and increases cellular trafficking. Multidomain misfolding clearly plays a role in the molecular pathology of CF, thus, a more detailed understanding of this process as globally outlined above is required to generate novel ways to rescue mutant CFTR.Item Cystic fibrosis(1994-02-03) Stone, Dennis K.Item Cystic fibrosis in adults(1986-05-01) Robertson, K. JoyItem Cystic Fibrosis: the path to a cure(2013-02-22) Jain, RakshaItem Cystic Fibrosis: the search for the gene and the cellular defect(1989-10-12) Westergaard, HenrikItem Masqueraders for Appendicitis(2015-01-26) Farzal, Zehra; Khan, N.; Cope-Yokoyama, S.; Fischer, A.C.INTRODUCTION: Patients with cystic fibrosis (CF) are often subject to pulmonary infections treated with antibiotics such as aminoglycosides which have the side effect of sensorineural hearing loss (SNHL). Since children with CF are often on prolonged courses and/or higher doses, they are particularly at risk. OBJECTIVE: To review the role of routine hearing screening for SNHL in children with CF who have been on aminoglycoside therapy. DATA SOURCES: PubMed, Cochrane, SCOPUS, and OVID databases REVIEW METHODS: A systematic review of the literature was performed in accordance with PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. A comprehensive PubMed MeSH search of the English language literature with human subjects only was performed to include all indexed years and the search strategy was adapted to the additional databases. Results: Twelve studies (1979-2014) were included in the review. Three of the 12 articles also studied adult CF patients. The study population included 762 children (age range, 5 months-20 years). Objective hearing screening measures included pure tone audiometry (PTA) at standard ± high frequency threshold (12/12), distortion product otoacoustic emissions (DPOAE) (4/12), transient-evoked otoacoustic emissions (1/12), and automated auditory brainstem response (AABR) (1/12). The overall prevalence of SNHL ranged from 0% to 29%. In a subset of children with high levels of exposure, up to 44% had SNHL. Eight studies recommended hearing screening in CF children on aminoglycosides of which 2 studies recommended screening regardless of aminoglycoside exposure. Four studies made no recommendations and in three of these, the children had a short course of aminoglycosides. HFPTA was the most commonly recommended screening measure followed by DPOAEs. CONCLUSION: Hearing screenings are quick and inexpensive measures leading to interventions that can prevent significant cognitive and linguistic developmental difficulties in children secondary to hearing loss. Routine hearing screening in children with CF exposed to aminoglycosides is supported by the current literature based on the high prevalence of SNHL in this population. Future studies should define the optimal timing for hearing screening during and after aminoglycoside therapy.Item [Southwestern News](2001-03-01) Cofer, BrianItem Transitions of care in cystic fibrosis(2021-06-11) Cohen, Leah