Mentor: John Engelhardt, Ph.D.
Lab Phone: 335-9613

Molecular Mechanisms of Submucosal Gland Morphogenesis

Identifying Stem Cells in the Lung As Targets for Gene Therapy

Since the field of gene therapy continues to hold promise for cures of genetic diseases, clinical trials are currently underway to determine the efficacy of viral-mediated gene therapy. One of the hottest areas in gene therapy is cystic fibrosis research, which is the most common genetic disorder in Caucasians. This disease, which has become a model genetic disease in the lung for testing gene therapy approaches, is the disease on which my research is focused. In order for gene therapy to be successful, certain fundamental problems must be resolved. One problem involves achieving properly regulated, long-term expression of a corrected gene. Targeting delivery of a therapeutic gene to adult stem cells in the lung can provide a partial solution to this problem. However, in order to target stem cells, we need to identify and characterize the stem cells thought to reside in niches in protected areas within the lung. One of these protected areas is the submucosal gland within human airways. This mini-organ is the primary structure that produces mucus and antibacterial factors that help combat infection from external factors within the lung. It is also a region that has a high expression of cystic fibrosis transmembrane conductance regulator (CFTR), the protein that is mutated in cystic fibrosis patients. Hence, targeting stem cells in this area can result in long-term CFTR correction. Consequently, my projects are geared toward defining the stem cells of the lung and understanding the developmental/post-developmental signal transduction pathways involved in controlling stem cell proliferation within the lung. Our lab is using transgenic mouse models and recombinant viruses that express transgenes to study these cells and pathways.

Abstracts:

Driskell , R.R., Liu, X., Luo, M., Filali, M., Abbatt, D., Chen, N. and Engelhardt, J. Characterization of a Lef-1 promoter segment that facilitates inductive developmental expression in mouse tissues, 52nd Annual Montagna Symposium on the Biology of Skin: Stem Cells in Skin; June 13-17, 2003, Snowmass Village, CO

Driskell , R.R., Liu, X., Luo, M., Filali, M., Abbatt, D., Chen, N., and Engelhardt, J. Characterization of a Lef-1 promoter segment that facilitates inductive developmental expression in mouse tissues, Annual Wnt Meeting; May 20-23 2004, University of Michigan, Ann Arbor, MI.

Driskell, R.R., Goodheart M., Neff T., Liu L., Moothart C., and Engelhardt J.F., Wnt3a-mediated Induction of Lef-1 is Required for Maintenance, But Not Initiation, of Submucosal Gland Morphogenesis. Keystone Symposia: Wnt and beta-Catenin Signaling In Development and Disease April 7-12, 2006, Snowbird, UT

Driskell, R.R., Goodheart, M., Neff T., Liu L., Luo M., Moothart C., Hosokawa R., Chai Y., and Engelhardt J.F., Wnt3a Regulates Lef-1 Expression During Airway Submucosal Gland Morphogenesis. North American Cystic Fibrosis Conference, Denver Co, Nov 3, 2:20pm; W22. Model Systems For Cystic Fibrosis Disease

Driskell, R.R., Goodheart M., Neff T., Liu X., Zhang, Y., Zhou W., and Engelhardt J.F., Stem Cell Niches in the Ferret Proximal Airway. North American Cystic Fibrosis Conference, November 2-5, Denver, CO

Publications:

Driskell RR, Goodheart M, Neff T, Liu X, Luo M, Moothart C, Sigmund CD, Hosokawa R, Chai Y, Engelhardt JF. Wnt3a regulates Lef-1 expression during airway submucosal gland morphogenesis. Dev Biol. 2007 May 1;305(1):90-102. Epub 2007 Feb 7. PubMed PMID: 17335794; PubMed Central PMCID: PMC1892170.

Liu X, Driskell RR, Engelhardt JF. Stem cells in the lung. Methods Enzymol. 2006;419:285-321. Review. PubMed PMID: 17141060; PubMed Central PMCID:PMC1803078.

Liu X, Driskell RR, Engelhardt JF. Airway glandular development and stem cells. Curr Top Dev Biol. 2004;64:33-56. Review. PubMed PMID: 15563943.

Liu X, Driskell RR, Luo M, Abbott D, Filali M, Cheng N, Sigmund CD, Engelhardt JF. Characterization of Lef-1 promoter segments that facilitate inductive developmental expression in skin. J Invest Dermatol. 2004 Aug;123(2):264-74. PubMed PMID: 15245424; PubMed Central PMCID: PMC1803077.

Driskell RR, Liu X, Luo M, Filali M, Zhou W, Abbott D, Cheng N, Moothart C, Sigmund CD, Engelhardt JF. Wnt-responsive element controls Lef-1 promoter expression during submucosal gland morphogenesis. Am J Physiol Lung Cell Mol Physiol. 2004 Oct;287(4):L752-63. Epub 2004 Jun 11. PubMed PMID: 15194563.

Liu X, Yan Z, Luo M, Zak R, Li Z, Driskell RR, Huang Y, Tran N, Engelhardt JF. Targeted correction of single-base-pair mutations with adeno-associated virus vectors under nonselective conditions. J Virol. 2004 Apr;78(8):4165-75. PubMed PMID: 15047832; PubMed Central PMCID: PMC374254.

Driskell RA, Engelhardt JF. Current status of gene therapy for inherited lung diseases. Annu Rev Physiol. 2003;65:585-612. Epub 2002 May 1. Review. PubMed PMID: 12524461; PubMed Central PMCID: PMC1857313.