To focus of our laboratory is abnormalities of the airway epithelial cell differentiation that characterize many lung diseases including bronchitis, bronchiectasis, respiratory virus infection, chronic bacterial infection, and bronchogenic carcinoma. We are particularly interested in mechanism of ciliogenesis in airway epithelial cells. To understand the molecular mechanisms that regulate normal pulmonary epithelial cell growth and differentiation in disease, we are investigating airway epithelial cell growth and differentiation in the developing lung, in a primary culture system of fully differentiated mouse airway epithelial cells that we developed, and lung infection models. We then use these information to determine how normal pathways are altered during infection and injury. Infection with influenza virus and Pseudomonas aeruginsa are studied in our models as these are leading causes of respiratory virus infection and nosocomial bacteria infections respectively.
We are particularly interested in regulatory molecules, and have previously characterized a transcription factor called foxj1. This factor is a member of the forkhead family of transcription factors and has central roles in regulating epithelial cell differentiation. It is expressed in ciliated cells and T cells. Foxj1 is required for ciliogenesis and the organization of proteins that bind to the apical membrane important in host defense and signaling. We have generated a mouse that is deficient Knock out mouse in this gene and found that the mouse has situs inversus and absent ciliogenesis, mimicking the human Kartegener's syndrome. Current genetic analyses are directed toward understanding the regulation of ciliogenesis and the apical membrane of the airway epithelial cell as it comes into contact with the airway lumen. Here, whole genome analysis using microarray methodologies, combine with confocal microscopy to examine cell-specific gene expression at the protein level are utilitzed. These studies are linked to disorders of epithelial cell differentiation such as primary ciliary dyskinesis, cystic fibrosis, bronchiectasis, and asthma.
1. Lesimple P, I van Seuningen, MP Buisine, MC Copin, M Hinz, W Hoffmann, R Hajj, SL Brody, C Coraux, E Puchelle. Trefoil factor family 3 peptide promotes human airway epithelial ciliated cell differentiation. Am J Respir Cell Mol Biol. 36:296-303. 2007
2. Schuster, DP, Brody, SL, Zhou, Z, Bernstein, M, Arch, R, Link, D, Mueckler, M. Regulation of lipopolysaccharide-induced neutrophil glucose uptake. Am J Physiol Lung Cell Mol Physiol. 2007 Apr;292(4):L845-51. Epub 2006 Nov 22.
3. Zhang, Y, G Huang, LP Shornick, WT Roswit, JM Shipley, SL Brody, MJ Holtzman MJ. A transgenic FOXJ1-Cre system for gene inactivation in ciliated epithelial cells. Am J Respir Cell Mol Biol. 36:515-9, 2007.
4. Pan, J, Y You, T Huang, SL Brody. RhoA-mediate apical actin enrichment is required for ciliogenesis and is promoted by Foxj1. J Cell Sci, 120:1868-76, 2007.
5. Ferkol, T, H Mitchison, C O'Callaghan, M Leigh, J Carson, H Lie, D Rosenbluth, S L Brody. Current issues in the basic mechanisms, pathophysiology, diagnosis, and management of Primary Ciliary Dyskinesia. In: Respiratory Disease in Infants and Children, U. Frey and J. Gerritsen (Eds). European Respiratory Society Mongraph 37, 2006, pp. 291-313.
6. Driscoll JA, Brody SL, Kollef MH. The Epidemiology, Pathogenesis and Treatment of Pseudomonas aeruginosa. Infections and.Drugs. 2007; 67(3):351-68.
7. Brody SL and JJ Atkinson, Epithelial Repair and Regeneration. In: Molecular Pathology of Lung Diseases, P. Cagle, D. S. Zander, J. Jagirdar, R. Barrios, A. Haque and H. Popper (eds). Spring, New York, 2007
8. LeSimple, P, I van Suningen, MP Buisine, MC Copin, S Brody, M Hinz, W Hoffmann, R Hajj, C Coraux, E Puchelle. The trefoil factor TFF3 promotes human airway epithelial ciliary differentiation. Annual CFF Meeting, 2006. Pediatric Pulm Suppl. 2006.
9. Driscoll JA, Saito M, You Y, Schlesinger P, Brody SL. Evaluation of primary cilia as flow sensors in airway epithelial cells. Am J Resp and Crit Care Med, 2007.
10. Zhang, Y, Huang, G, Shornick, LP, Roswit, WT, Shipley, M, Brody, SL, and Holtzman, MJ.. Transgenic FOXJ1-Cre mediates recombination in ciliated cells. Am J Resp and Crit Care Med 2007.