One of first uses of cultured epithelia to explore CF

Localizes CF defect to a loss of chloride permeability in apical membrane of airway epithelia

Focuses attention on a chloride transport

Expressing recombinant CFTR in CF cells corrects the CF chloride defect

Demonstrates causal relationship between mutations in CFTR gene and physiological hallmark of CF

Fuorescence microscopic assay suggests strategy for screening potential therapeutics

Discovery that CFTR is a chloride channel

Links genetic defect and physiological defect

Enables studies of CFTR function

Provides strategy for high throughput screens to develop drugs targeting CFTR

Discovery of complex regulation of CFTR channels

Regulation by ATP at nucleotide-binding domains and by phosphorylation of R domain

Sets stage to modify CFTR regulation pharmacologically

Discovery that CF airways fail to secrete bicarbonate

Sets stage for exploring role of airway surface liquid pH in pathogenesis

Reducing incubation temperature partially rescues CFTR-ΔF508 processing and function

Ignites efforts to develop pharmaceuticals to correct mutant CFTR

Classification scheme describes how CFTR mutations disrupt function

Facilitates understanding of genotype-phenotype relationships

Provides roadmap to develop mutation-specific treatments

First report of gene transfer to people with CF

Suggests gene therapy is feasible. But, gene transfer is inefficient

Initiates attempts to identify barriers to gene transfer

Identified individual barriers to efficient gene transfer

Guides efforts to circumvent inefficiencies and improve gene transfer

First report of gene transfer to people with CF using a non-viral vector

Establishes feasibility, but also reveals inefficiencies

Discovery that bacteria in CF lungs live in biofilms

Explains why CF infections are so resistant to treatment

Suggests new therapeutic strategies

Identifies two distinct enzymatic activities that control gating

Reveals novel molecular mechanism that may be a therapeutic target

First mammalian disease model other than mice

Provides opportunities to investigate pathogenesis and test new treatments

CF pigs develop lung disease that mirrors that in humans

Exhibit host-defense defect against bacteria beginning at birth

Resolves chicken and egg conundrum; infection precedes inflammation

Enables investigation of pathogenesis and therapeutics

Second animal model of disease

Enable studies of disease mechanisms and new treatments

Enable studies of therapeutics targeting the common CF mutant

CF airway surface liquid is acidic

Acidity inhibits antimicrobials and impairs killing of bacteria

Links loss of CFTR bicarbonate secretion to host defense defect

Increasing airway liquid pH might be beneficial

CF ferrets and pigs develop CF-related diabetes mellitus

Provides new opportunity to understand an increasingly frequent complication as people with CF live longer

Mucociliary transport is defective in CF beginning at birth

Mucus sometimes fails to detach from submucosal glands, thereby inhibiting mucociliary transport

Results identify new therapeutic strategies

Develops genomic signature-based approach as novel CF discovery strategy

Identifies small molecules with the potential to rescue ΔF508-CFTR