John
F. Engelhardt, Ph.D.
Director of the Center for Gene Therapy
Professor and Head, Department of Anatomy and Cell Biology
Link
to the Engelhardt Lab web site
Training:
B.S., Iowa State University, Ames, IA (Biochemistry), 1985
Ph.D., Johns Hopkins University, Baltimore, MD (Human Genetics), 1990
Research Associate, University of Michigan, Ann Arbor, MI (HHMI), 1992
Research Associate, University of Michigan, Ann Arbor, MI (Internal Medicine), 1993
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Research Focus: Research in the Engelhardt laboratory focuses on the molecular basis of inherited and environmentally induced diseases, and on the development of gene therapies for these disorders. Included are two major research areas: 1) the study of lung molecular and cellular biology as it relates to the pathogenesis and treatment of cystic fibrosis (CF) lung disease, and 2) the molecular mechanism underlying redox-mediated injury and the development of molecular therapies for ischemia/reperfusion injury, sepsis, and the neurodegenerative disease amyotrophic lateral sclerosis (ALS). Research on lung biology includes the study of adult epithelial stem cells and their niches in the airway, and dissecting the pathogenesis of lung disease in animal models of cystic fibrosis. The laboratory is currently elucidating transcriptional signals important for early establishment of the airway glandular stem cell niche, and for mobilization of stem cells from this niche following airway injury. The newly generated ferret and pig models of cystic fibrosis are being used to understand how stem cells in the adult airway respond to injury resulting from dysfunction of CFTR (the chloride channel that is defective in cystic fibrosis). These new genetic models of CF are also being used to dissect pathophysiologic mechanisms of disease and to develop gene therapies that target the lung with recombinant adeno-associated virus. A second area of interest is the development of pharmacologic and gene-based therapies for redox-dependent disorders of the liver and spinal cord. Such studies are aimed at the treatment of environmentally induced liver injuries—those resulting from sepsis, ischemia/reperfusion, and (in the case of ALS) motor neuron injury. We are using rodent transgenic and knockout models to better understand the mechanisms that are involved in inflammation and injury and are controlled by reactive oxygen species. Of particular interest in this area are mechanisms of redox-regulated NFkB activation via several NADPH oxidase complexes (Nox1, Nox2 and Nox4), whose roles include generating intracellular superoxides in response to extracellular pro-inflammatory cytokine signals (IL-1beta and TNFalpha pathways are a major focus). This redox-signaling program heavily utilizes recombinant viral vectors, transgenic/knockout mice, and proteomic approaches to address basic aspects of pathophysiology, and also to generate new therapies capable of promoting organ regeneration and repair while also minimizing the deleterious inflammatory responses to injury.
Selected Publications: Spencer, NY, Yan, Z, Boudreau, RL, Zhang, Y, Luo, M., Li, Q., Tian, X., Shah, A.M., Davisson, R.L., Davidson, B., Banfi, B. and Engelhardt, J.F. (2011). Control of hepatic nuclear superoxide production by glucose 6-phosphate dehydrogenase and NADPH oxidase-4, The Journal of Biological Chemistry, 286(11), 8977-8987. Sun, X., Sui, H., Fisher, J.T., Yan, Z., Liu, X., Cho, H-J., Joo, N.S., Zhang,Y., Zhou,W., Yi,Y., Kinyon, J.M., Lei-Butters, D.C., Griffin, M.A., Naumann, P., Luo, M., Ascher, J., Wang, K., Frana, T., Wine, J.J., Meyerholz, D.K., and Engelhardt, J.F. (2010). Disease phenotype of a ferret CFTR-knockout model of cystic fibrosis. J. Clinical Invest. 120(9), 3149-3160. PMCID: 2929732 Oakley, F.D., Smith, R.L., and Engelhardt, J. (2009) Lipid Rafts and Caveolin-1 Coordinate IL-1b-Dependent Activation of NFkB by Controlling Endocytosis of Nox2 and IL-1R1 from the Plasma Membrane. J Biol Chem. 284:48, 33255–33264. PMCID: 2785168 Liu, X., Luo, M., Guo, C., Yan, Z., Wang, Y., Lei-Butters, D.C. and Engelhardt, J.F. (2009). Analysis of Adeno-Associated Virus Progenitor Cell Transduction in Mouse Lung. Molecular Therapy, 17(2), 285-293. PMCID: 2665184 Harraz, M.M., Marden, J.J., Zhou, W., Zhang, Y., Williams, A., Sharov, V.S., Nelson, K., Luo, M., Paulson, H., Schoneich, C., and Engelhardt, J.F. (2008). SOD1 mutations disrupt redox-sensitive Rac regulation of NADPH oxidase in a familial ALS model. J Clin Invest 118: 659-670. PMCID: 2213375 Sun, X., Yan, Z., Yi, Y., Li, Z., Lei, D., Rogers, C.S., Chen, J., Zhang, Y., Welsh, M., Leno, G.H. Engelhardt, J.F. (2008) AAV Targeted Disruption of the CFTR Gene in Cloned Ferrets. J. Clinic Invest 118:4, 1578-1583. PMCID: 2263147 |
Link to a complete list of Dr. Engelhardt's peer-reviewed journal articles