Director: Martina Gentzsch, Ph.D.
Co-Director: Wanda O’Neal, Ph.D.

The Pre-Clinical Core
The Pre-Clinical Core is designed to provide services to analyze the
efficacy of treatments that target different stages in the pathogenic
sequelae of CF disease development.

To support urgently required translational Cystic Fibrosis (CF) research, the Pre-Clinical Core of the University of North Carolina CF Research and Translation Core Center is pursuing the following objectives:

  1. Evaluation of pre-clinical drug candidates in vitro in primary human airway and intestinal planar epithelial CF cultures by measurement of ion transport, CFTR maturation and surface expression, drug pharmacokinetics, and airway surface liquid properties.
  2. Evaluation of pre-clinical drug candidates ex vivo in organoid models (i.e. colonospheres, nasospheres, and bronchospheres) and various epithelial tissues (mouse distal colon, jejunum, gallbladder, trachea, bronchi, nasopharnyx, and human rectal biopsies). Services provided are quantitative organoid swelling assays, functional assessment of ion transport in tissues, and biochemical assessment of CFTR rescue in organoids and tissues.
  3. Evaluation of pre-clinical drug candidates in vivo in relevant mouse models of CF and other lung diseases using a variety of assays to determine the efficacy of therapeutic treatments on ion transport defects, CFTR processing, defective mucus clearance, chronic infection, and inflammation. Services provided in this objective include mouse maintenance and distribution, pharmacological treatments, pharmacokinetic analyses, and phenotyping including collection of bronchoalveolar lavage, measurements of soluble mediators, airway mucus burden and clearance, nasal potential difference, salivary secretion rates, histopathology, morphometry, microbiology, and technologically advanced airway imaging.
Correction and Potentiation of CFTR.
Correction and Potentiation of CFTR. A. Correctors promote transfer of mutant CFTR from the ER to the apical membrane, whereas potentiators enhance activity of apical CFTR. B. Trafficking defect of ∆F508. Confocal immunofluorescence of apical wild-type and intracellular-retained ∆F508 CFTR (green) expressed as a virally introduced epitope-tagged variant in primary HBE cells. Cilia are stained in red and nuclei in blue. C. Processing defect of ∆F508 CFTR. Western blot of wild-type CFTR and ∆F508 detected in primary normal and CF (∆F508/∆F508) HBE cells.

While certain assays and models provided by the Core focus on restoration of CFTR function in CF, most of our services have broad applications to multiple research programs seeking therapeutic benefit for CF. These include approaches that utilize small-molecule pharmacological interventions, gene therapy, correction of airway surface liquid hydration and mucus clearance defects, normalization of ion transport, and inflammation/infection control.

The availability of models and assays by the Pre-Clinical Core will provide a translational bridge that will support the rapid transfer of emerging drug candidates from the research laboratory to therapies for CF patients.

Pre-Clinical Core key investigators:

Martina Gentzsch, Ph.D.
Wanda O’Neal, Ph.D.
Alessandra Livraghi-Butrico, Ph.D.
Barbara Grubb, Ph.D.
Charles Esther, M.D., Ph.D.
Michael Chua, Ph.D.

Acknowledgement:

Funded by the NIH/NIDDK (P30 DK065988)

Contact Information

Martina Gentzsch, Ph.D.
Associate Professor, Department of Cell Biology and Physiology
Director, Pre-Clinical Core
Director, CFTR Functional Analysis Core
Marsico Lung Institute/Cystic Fibrosis Research Center
The University of North Carolina
1121 Marsico Hall CB 7248
125 Mason Farm Road
Chapel Hill, NC 27599
Phone: (919) 966-7058
Fax: (919) 966-5178
E-mail: