CFTR protein expression in well-differentiated human bronchial epithelial cultures. Well-differentiated cultures derived from human bronchial epithelial tissues were immunostained with CFTR and tubulin antibodies and analyzed on a Leica SP2 laser confocal microscope. The image represents an overlay of the DIC (grayscale), CFTR (red), cilia (tubulin, green), and nuclei (DAPI, blue) confocal planes, and depicts an epithelial cell sheet that contains a group of ciliated cells surrounding a goblet cell (bottle-shaped cell with no cilia). CFTR is expressed only at the apical membrane of ciliated cells, but not goblet cells. Magnification x190. Reproduced from Kreda et al 2005 Miol Biol Cell 16, 2154 with permission of ASCB / MBC.
The Marsico Lung Institute (MLI) at the University of North Carolina at Chapel Hill traditionally has had a single goal: to “cure” CF lung disease. To this end, we assembled a broad-based biomedical research team to tackle this goal. Thus, we have wide-ranging skills in ion transport physiology (Ussing chamber, patch clamp, confocal surface liquid imaging), mucus cell/mucin secretion biology and biochemistry, transgenic and gene-targeted mouse models, in vivo measures of mucociliary clearance and measures of mucin concentration/hydration, and Phase I clinical trials. In addition, we have added expertise focused on specific CF microbiologic problems of the lung, including Pseudomonas aeruginosa, anaerobic bacteria, and now Burkholderia cepacia. These efforts are complemented by a major effort to identify genetic modifiers of all facets of CF airways pathogenesis. Thus, the airways pathobiology/therapeutics efforts have produced multiple collaborations within the UNC MLI, multiple national/international collaborations, and indeed, collaboration with the CFF Mucus Consortium and Gene Modifier groups.
With the arrival on the UNC campus of Dr. Jack Riordan and his group and Dr. Doug Cyr, we have become a more broad and ‘mature’ MLI, i.e., we have developed as a second UNC MLI goal: to define the abnormalities in mutant CFTR biogenesis/trafficking, to develop the appropriate primary screens and secondary screens for mutant CFTR “potentiator/corrector” hit/lead evaluation, and to refine the clinical biophysical and biochemical assays needed for “potentiator/corrector” drug development. Again, this effort has melded together collaborative UNC CF Center groups focused on CF genetics, CFTR biochemistry and cell biology, high throughput drug screening paradigms, animal models of CF, and clinical development/validation of both nasal and rectal biophysical and biochemical analyses of correction of mutant CFTR processing defects.
Thus, the UNC MLI has now been organized to provide the maximum technical and intellectual support to both goals, with a common focus on the rapid “translation” of basic science insights into the clinical patient care arena. The centerpiece of the UNC MLI is the network of Core Laboratories that underpin all CF research at UNC. As a group, the Cores operate under two common themes. First, the Cores provide access for UNC CF investigators to a broad range of quality-controlled, diverse reagents and technologies. Second, the Cores provide a strong intellectual/research contribution to the UNC MLI by virtue of the fact that the Cores are led by talented and productive scientists. Indeed, our three major Cores ( the Tissue Procurement and Cell Culture Culture Core, the Molecular Biology Core, and the Mouse Models Core) have become resources to universities both nationally and internationally, and indeed to CFFTI and industry collaborators, to make available reagents and expertise to CF investigators in need of cellular, molecular, and mouse reagents.
The Marsico Lung Institute achieves its purpose through:
- Core laboratories that provide training, technical support, laboratory animals, or assays;
- A pilot/feasibility program that offers startup funds to junior investigators or to established investigators who wish to pursue new directions in research;
- A scientific enrichment program, that improves the intellectual climate for gastrointestinal biological research and promotes cooperation, collaboration, and communication among involved personnel; and
- A professional development and training program that promotes the development of junior faculty.
-Dr. Richard C. Boucher, Kenan Professor of Medicine, Director of Marsico Lung Institute
Cystic Fibrosis (CF) is the most common lethal genetic disease in the Caucasian population, affecting one in 3300 births. Other ethnic populations are affected less frequently, ranging from one in 10,000 - 15,000 births in Hispanic and African-American populations to one in 30,000 Asian births. The CF gene codes for a protein responsible for controlling salt and water transport across the cells lining the lung, pancreas, and other organs. When this gene is abnormal, secretions in these organs become dehydrated and sticky, and eventually clog airways. Abnormal secretions may also block other organs (pancreas, intestines, male reproductive tract, bile ducts) as well. CF patients have a number of common symptoms, which may include: salty-tasting skin; persistent coughing, wheezing, or recurrent pneumonia; failure to gain weight despite a big appetite; and frequent, bulky stools. The standard test used to diagnose CF is the sweat test, which very simply and painlessly measures the amount of salt in sweat. Direct testing for abnormalities in the CF gene (from a blood sample) is possible most of the time.
Treatment for CF is based upon clearing the thick build-up of secretions in the airway using chest percussion (e.g. clapping hands on the back and chest), inhaled treatments, and exercise. Antibiotics to fight the particular bacteria typically associated with chest infection in CF patients are used when the amount of infection becomes problematic, and may be administered by mouth, inhaled, or intravenously. The maintenance of proper nutrition is also essential: a high calorie diet, supplementation of certain vitamins, and the use of enzymes that help to digest meals are all necessary.