Cystic fibrosis investigators within the P30 Center require access to expertise and specialized equipment for their studies of CFTR expression and function. For both established CF laboratories and those new to CF research, a need has been identified for developing novel cell lines expressing mutant and wild type CFTR, and for dedicated equipment and biophysical protocols necessary to assess CFTR function. In particular, we propose two specific aims:
Specific Aim 1. Cellular models expressing wild type and mutant CFTR will be developed and provided by Core A. These will include primary cells from murine lungs and novel lentiviral-transduced cell lines. The latter include innovative cell models useful for CFTR proteomic and structural studies and for high throughput screens to discover the next generation of CF drugs.
Specific Aim 2, Assistance, equipment and expertise necessary to perform functional assays of CFTR in the above cell models (Aim 1) will include biophysical techniques (patch clamp). These assays are required to test the efficacies of new maneuvers to rescue mutant CFTR channel activity and regulation as well as to define the underlying mechanisms. The Core will aid in the development/validation of new CF cell models;provide primary murine airway epithelial cells encoding specific CFTR mutations;and assist investigators with their experiments to test the effects of new maneuvers on mutant CFTR (e.g., DeltaF508) protein stability and channel function. Collaborative studies involving proteomic studies of CFTR post-translational modifications, discovery of peptides from the first cytosolic loop of CFTR that specifically block NBD1-TMD1 binding and numerous other NIH funded projects will also be assisted by the Core. Core A will foster interdisciplinary research by providing valuable new cell models and assays of CFTR expression and function to investigators less familiar with the requisite techniques, and contribute to innovative studies of CF pathogenesis and experimental therapy.

Public Health Relevance

Cystic fibrosis (CF) is one of the most common lethal genetic disorders in this country. Currently there are no effective treatment options. This research core provides cell models and functional assays that are essential for testing, validating and refining new CF therapies being developed by P30 investigators.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Center Core Grants (P30)
Project #
2P30DK072482-06
Application #
8320677
Study Section
Special Emphasis Panel (ZDK1-GRB-7 (J1))
Project Start
Project End
Budget Start
2012-05-01
Budget End
2013-04-30
Support Year
6
Fiscal Year
2012
Total Cost
$232,435
Indirect Cost
$73,776
Name
University of Alabama Birmingham
Department
Type
DUNS #
063690705
City
Birmingham
State
AL
Country
United States
Zip Code
35294
Wang, Wei; Hong, Jeong S; Rab, Andras et al. (2016) Robust Stimulation of W1282X-CFTR Channel Activity by a Combination of Allosteric Modulators. PLoS One 11:e0152232
Mutyam, Venkateshwar; Libby, Emily Falk; Peng, Ning et al. (2016) Therapeutic benefit observed with the CFTR potentiator, ivacaftor, in a CF patient homozygous for the W1282X CFTR nonsense mutation. J Cyst Fibros :
Wei, Shipeng; Roessler, Bryan C; Icyuz, Mert et al. (2016) Long-range coupling between the extracellular gates and the intracellular ATP binding domains of multidrug resistance protein pumps and cystic fibrosis transmembrane conductance regulator channels. FASEB J 30:1247-62
Ehrhardt, Annette; Chung, W Joon; Pyle, Louise C et al. (2016) Channel Gating Regulation by the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) First Cytosolic Loop. J Biol Chem 291:1854-65
Roy, Bijoyita; Friesen, Westley J; Tomizawa, Yuki et al. (2016) Ataluren stimulates ribosomal selection of near-cognate tRNAs to promote nonsense suppression. Proc Natl Acad Sci U S A 113:12508-12513
Mutyam, Venkateshwar; Du, Ming; Xue, Xiaojiao et al. (2016) Discovery of Clinically Approved Agents That Promote Suppression of Cystic Fibrosis Transmembrane Conductance Regulator Nonsense Mutations. Am J Respir Crit Care Med 194:1092-1103
Bali, Vedrana; Lazrak, Ahmed; Guroji, Purushotham et al. (2016) Mechanistic Approaches to Improve Correction of the Most Common Disease-Causing Mutation in Cystic Fibrosis. PLoS One 11:e0155882
Veit, Gudio; Avramescu, Radu G; Chiang, Annette N et al. (2016) From CFTR biology toward combinatorial pharmacotherapy: expanded classification of cystic fibrosis mutations. Mol Biol Cell 27:424-33
Solomon, George M; Raju, S Vamsee; Dransfield, Mark T et al. (2016) Therapeutic Approaches to Acquired Cystic Fibrosis Transmembrane Conductance Regulator Dysfunction in Chronic Bronchitis. Ann Am Thorac Soc 13 Suppl 2:S169-76
Bali, Vedrana; Lazrak, Ahmed; Guroji, Purushotham et al. (2016) A synonymous codon change alters the drug sensitivity of ΔF508 cystic fibrosis transmembrane conductance regulator. FASEB J 30:201-13

Showing the most recent 10 out of 117 publications