Zea Borok Professor Medicine, Biochemistry & Molecular Biology Keck School of Medicine

Education:
MBChB 1979 Medicine - University of Cape Town, South Africa

Postdoctoral Research Fellowship:
1981 - 1982 College of Physicians and Surgeons of Columbia University

Started at USC: 1990

Research Topics: Gene Regulation/Transcription, Gene Therapy, Stem Cell Biology

Research Description

My research is focussed on dissecting transcriptional mechanisms that regulate differentiation of lung alveolar epithelial cells in the context of lung injury and repair. The normal alveolar epithelial lung lining consists of two highly differentiated cell types, type II and type I cells. Type II cells normally serve as progenitors for themselves and also give rise to type I cells, whereas type I cells have been viewed as being terminally differentiated. Failure of type II cells to give rise to type I cells may give rise to abnormal repair of the lung leading to failure of re-epithelialization and pulmonary fibrosis. Using an in vitro culture model, we have demonstrated that isolated type II alveolar epithelial cells in culture undergo transdifferentiation towards a type I cell phenotype recapitulating the situation in vivo following injury. Furthermore, the transdifferentiation process is reversible by certain culture conditions indicating that maintenance of alveolar epithelial cell phenotype is actively regulated and suggesting considerable plasticity of alveolar epithelial cell phenotype. The molecular mechanisms that regulate transitions between the two cell types in the adult have not been elucidated. We are investigating the role of the transcriptionfactors GATA-6 and FoxP2 on regulating expression of the differentiated alveolar epithelial cell phenotype and on modulating phenotypic transitions between type II and type II cells. To do this, we are investigating interactions of these transcription factors with cell-specific genes, aquaporin-5 and surfactant protein-C, and evaluation effects of overexpression of inhibition of these factors on cell phenotype. In addition, we have recently demonstrated that alveolar epithelial cells treated with TGF-ß undergo epithelial-mesenchymal transition to a myofibroblast phenotype and have initiated studies to determine the transcriptional mechanisms underlying this phenotypic change with particular emphasis on interaction between TGF-ß and Wnt/ß-catenin pathways.