BS: Illinois Wesleyan University, Bloomington, IL (1970); MS: Northwestern University. Chicago, IL; PhD: Northwestern University Chicago, IL (1974)
- Ion and water transport across epithelia (primarily airway and intestinal)
- Use of mouse models for ion transport study
- Comparative physiology (cardiopulmonary)
Alterations in transepithelial salt (and thus water) absorption and secretion result in a number fatal or debilitating diseases in variety of epithelial tissues. In airway epithelia, the rate of Na+ absorption and Cl- secretion and the concomitant water transport are important in determining the depth of the airway surface liquid that bathes the airway epithelia. Maintaining the optimal depth of this thin liquid layer for mucociliary clearance appears important for airway defense against pathogens. When the depth of the liquid layer is altered, as in cystic fibrosis (CF), severe disease results.
In intestinal epithelia, a balance between absorption and secretion is necessary to maintain the liquidity of intestinal contents necessary for proper digestion, enzymatic action, and mucus production. In intestine, defective regulation of secretion underlies major intestinal pathophysiology ranging from diarrhea (hypersecretion) to cystic fibrosis (hyposecretion). Control of transepithelial salt (Cl- secretion and Na+ absorption) and water transport across airway and intestinal epithelia is the major focus of my research interests.
In cystic fibrosis, a defect in the cAMP regulated Cl- channel (CFTR) is responsible for the airway and intestinal disease phenotype exhibited by humans with the disease. With the generation of the CF mouse model in l992 (Dr. Bev Koller and colleagues), we have been able to compare and contrast the human and murine disease. We have found that with respect to airway epithelia, the disease produces a remarkably different phenotype in the human and the mouse, with the former having severe lung disease and the latter exhibiting little or no lower airway disease.
The intestinal tract of the CF mouse exhibits relatively severe pathophysiology as a result of the secretory defect. Study of intestinal ion transport in both the adult and neonatal cystic fibrosis mouse has revealed some striking similarities to the human disease. Comparison of transepithelial ion transport mechanisms in epithelia from airway and intestinal tissues (from mouse and human) has given us insight into the disparity of disease phenotypes between tissue and species.
Transport studies in my laboratory have also focused on other mouse models in which various ion transport pathways (or receptors for ligands activating these pathways) have been genetically altered (primarily in collaboration with Dr. Bev Koller). These mice are beginning to provide clues as to why alterations in certain transport pathways result in a much more severe disease phenotype than those in others.
We use a number of different techniques (both in vivo and in vitro) to study transepithelial ion and water transport across airway and intestinal epithelial cells. In vitro ion and liquid transport are studied in cultured cells by employing a planar culture system as well as a cylindrical culture system (biofiber) that re-creates the geometric configuration of airways in vivo. In vivo nasal potential difference studies are performed on the upper airways of mice and from these measurements we can assess the ability of airway epithelia to transport Na+ and Cl-. This technique has been useful in assessing the outcome of gene transfer studies aimed at correcting the Cl- channel defect in CF mice. We have recently begun using in vivo microdialysis for the determination of airway surface liquid composition as well as the conentration of other components in the airway surface liquid. Ussing chambers are employed for studying the bioelectrics of ion transport in freshly excised neonatal and adult murine tissue.
The long-term goal of this research is to provide additional information into normal and abnormal ion and water transport physiology across epithelial cells (primarily airway and intestinal). This information will provide insight into how transport abnormalities lead to disease phenotypes and give clues into which therapeutic interventions can be employed to overcome these ion transport defects, thus restoring normal transepithelial salt and water homeostasis.