The overall goals of the SCOR are 1) to relate cystic fibrosis transmembrane regulator (CFTR) function(s) to the pathogenesis of CF lung disease, and 2) to design efficient and safe therapies for CF lung disease. The SCOR consists of four Projects and four Cores that utilize molecular biologic and physiologic techniques, and a recently generated CF """"""""knock-out"""""""" [CFTR (-/-)] mouse, to address these goals. Project IA (CFTR: Structure, Function, and Disease Pathogenesis, E. Price, P.I.) will characterize the topography of CFTR. Dr. Price combines heterologous expression systems for CFTR, epitope """"""""flagging"""""""" of CFTR domains, and the capability to generate novel high affinity monoclonal antibodies using purified CFTR and the CFTR(-/-) mouse. These studies are complemented by studies of Dr. Stutts (Mutational Analysis of CFTR Function, Project 1B) which will investigate structure/function relationships of mutated CFTRs expressed in heterologous and murine airway systems. Dr. Price (Project IA), assisted by Drs. Koller, Grubb, and Knowles, will close the loop with respect to CFTR function- pathogenesis by testing the effects of specific CFTR mutations in transgenic mice, using the CFTR(-/-) mouse as the background. Projects II and III focus on therapies of CF lung disease. Dr. Olsen (Project II, Retrovirus Mediated Gene Transfer into Airway Epithelia) will 1) identify mechanisms for increasing efficiency of retroviral entry into airway epithelial cells; 2) develop strategies to maintain gene expression in transduced airway epithelia; and 3) develop techniques for increasing airway epithelial cell proliferation in situ and """"""""depot"""""""" devices for retroviral delivery. Project III, (Therapy for CF Lung Disease, R. Boucher, P.I.) investigates cell biologic questions relevant to CF gene transfer in man. Questions to be investigated include defining: the cell types in the airway that express CFTR; the epithelial cell proliferation rates in normal and CF airways; and, the functional consequences of CFTR over-expression. A major series of studies will utilize the CFTR(-/-) mouse for developing therapies. Pharmacologic and gene transfer therapies, both transient and integrative, will be tested early and late in the course of CF lung disease. The SCOR is supported by four cores. The Administrative and Biostatistics Core (Core A, R. Boucher, P.I.) will perform administrative and data handling/analyses functions. The Tissue Culture Research Core (Core B, J. Yankaskas, P.I.) provides cellular material for investigators. The Mouse Core (Core C, B. Koller, P.I.) supplies CFTR(-/-) mice to investigators and houses transgenic mice expressing foreign CFTR cDNAs. The Morphology/Morphometry Core (Core D, M. Leigh, P.I.) will provide morphometric analyses of transgenic mice and CFTR(-/-) mice utilized in therapeutic protocols. The combination of in vitro and whole animal studies should yield important data to address major questions about CF pathogenesis and safe and efficient ways of treating CF lung disease.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Specialized Center (P50)
Project #
5P50HL042384-07
Application #
2220444
Study Section
Special Emphasis Panel (ZHL1-CSR-B (M2))
Project Start
1988-09-30
Project End
1998-08-31
Budget Start
1994-09-01
Budget End
1995-08-31
Support Year
7
Fiscal Year
1994
Total Cost
Indirect Cost
Name
University of North Carolina Chapel Hill
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
078861598
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
Coakley, Raymond D; Grubb, Barbara R; Paradiso, Anthony M et al. (2003) Abnormal surface liquid pH regulation by cultured cystic fibrosis bronchial epithelium. Proc Natl Acad Sci U S A 100:16083-8
Tarran, R; Grubb, B R; Gatzy, J T et al. (2001) The relative roles of passive surface forces and active ion transport in the modulation of airway surface liquid volume and composition. J Gen Physiol 118:223-36
Tarran, R; Grubb, B R; Parsons, D et al. (2001) The CF salt controversy: in vivo observations and therapeutic approaches. Mol Cell 8:149-58
Paradiso, A M; Ribeiro, C M; Boucher, R C (2001) Polarized signaling via purinoceptors in normal and cystic fibrosis airway epithelia. J Gen Physiol 117:53-67
Huang, P; Trotter, K; Boucher, R C et al. (2000) PKA holoenzyme is functionally coupled to CFTR by AKAPs. Am J Physiol Cell Physiol 278:C417-22
Matsui, H; Davis, C W; Tarran, R et al. (2000) Osmotic water permeabilities of cultured, well-differentiated normal and cystic fibrosis airway epithelia. J Clin Invest 105:1419-27
Bartlett, J S; Kleinschmidt, J; Boucher, R C et al. (1999) Targeted adeno-associated virus vector transduction of nonpermissive cells mediated by a bispecific F(ab'gamma)2 antibody. Nat Biotechnol 17:181-6
Grubb, B R (1999) Ion transport across the normal and CF neonatal murine intestine. Am J Physiol 277:G167-74
Noone, P G; Bennett, W D; Regnis, J A et al. (1999) Effect of aerosolized uridine-5'-triphosphate on airway clearance with cough in patients with primary ciliary dyskinesia. Am J Respir Crit Care Med 160:144-9
Paradiso, A M; Brown, H A; Ye, H et al. (1999) Heterogeneous responses of cell Ca2+ in human airway epithelium. Exp Lung Res 25:277-90

Showing the most recent 10 out of 63 publications