(Taken directly from the application) Despite profound implications for gene therapy of cystic fibrosis (CF), we are unsure which cell lineage model applies at the important small and large airway sites of CF lung disease progression. In model 1, which is pertinent to the hematopoietic system and epidermis, stem cells are relatively rare and most proliferation occurs in a transiently amplifying compartment which then generates terminal cells. In model 2, which theoretically may apply to the airway epithelium, there are no true stem cells in the classical sense but many of the non-terminal cells have great plasticity and are capable of extensive growth and differentiation when needed. The consequences for gene therapy are that in """"""""1"""""""" a permanent cure depends upon transfection of relatively few stem cells while in """"""""2"""""""" it is more important to target many cells. It is of immediate practical importance to identify and determine the topographic distribution of airway epithelial cells that have an extensive progenitorial capacity. To accomplish this, the following specific aims are proposed: 1) To test the hypothesis that proximal airway epithelial stem cells are confined to a distinct morphological compartment. 2) To determine which theoretical cell lineage model best applies to the pseudostratified airway epithelium of humans. 3) To test the hypothesis that there is a subcompartment of non-ciliated bronchiolar cells (Clara cells) that serve as stem cells. Specific subpopulations of airway epithelial cells from both transgenic animals and humans will be isolated and their proliferative capacity and differentiation potential will be determined. The proposed studies will establish the relationship between classic morphological cell type, expression of specific markers, proliferative capacity and differentiation potential. By rigorously testing the stem cell properties of specific airway epithelial cells we will develop a model for cell lineages and identify the most appropriate target cells for gene therapy of CF in the airways.
| Randell, Scott H (2006) Airway epithelial stem cells and the pathophysiology of chronic obstructive pulmonary disease. Proc Am Thorac Soc 3:718-25 |
| Chalermskulrat, Worakij; Neuringer, Isabel P; Park, Richard C W et al. (2004) PX3.102, a novel chinese herb extract, diminishes chronic airway allograft rejection. Transplantation 78:158-61 |
| Becker, Marie N; Sauer, Mariam S; Muhlebach, Marianne S et al. (2004) Cytokine secretion by cystic fibrosis airway epithelial cells. Am J Respir Crit Care Med 169:645-53 |
| Schoch, Kelly G; Lori, Adriana; Burns, Kimberlie A et al. (2004) A subset of mouse tracheal epithelial basal cells generates large colonies in vitro. Am J Physiol Lung Cell Mol Physiol 286:L631-42 |
| Davidson, Donald J; Gray, Michael A; Kilanowski, Fiona M et al. (2004) Murine epithelial cells: isolation and culture. J Cyst Fibros 3 Suppl 2:59-62 |
| Perez-Vilar, Juan; Randell, Scott H; Boucher, Richard C (2004) C-Mannosylation of MUC5AC and MUC5B Cys subdomains. Glycobiology 14:325-37 |
| Bruen, Kevin J; Campbell, Chris A; Schooler, Wesley G et al. (2004) Real-time monitoring of keratin 5 expression during burn re-epithelialization. J Surg Res 120:12-20 |
| Chalermskulrat, Worakij; Neuringer, Isabel P; Brickey, W June et al. (2003) Hierarchical contributions of allorecognition pathways in chronic lung rejection. Am J Respir Crit Care Med 167:999-1007 |
| Borthwick, D W; Shahbazian, M; Krantz, Q T et al. (2001) Evidence for stem-cell niches in the tracheal epithelium. Am J Respir Cell Mol Biol 24:662-70 |
| Randell, S H; Walstad, L; Schwab, U E et al. (2001) Isolation and culture of airway epithelial cells from chronically infected human lungs. In Vitro Cell Dev Biol Anim 37:480-9 |
Showing the most recent 10 out of 13 publications
