David H. Perlmutter, M.D.

Executive Vice Chancellor for Medical Affairs and Dean
Professor
Pediatrics

Molecular Cell Biology Program
Immunology Program
Molecular Genetics and Genomics Program

  • 8116

  • perlmutterd@wustl.edu

  • α1-antitrypsin deficiency, protein secretion, protein degradation, autophagy, proteostasis, autophagy enhancer drugs

  • Pathobiology of liver disease from accumulation and proteotoxicity of misfolded proteins in α1-antitrypsin deficiency; role of autophagy in biology and treatment of disorders caused by misfolded proteins

Research Abstract:

Dr. Perlmutter is internationally recognized for his research on the pathobiology of α1-antitrypsin deficiency, a rare disease in which a misfolded protein causes chronic liver failure and hepatocellular carcinoma. His work has led to advances in understanding the basic mechanisms of liver fibrosis and carcinoma and novel therapeutic strategies. Together with collaborators he has discovered a pipeline of drugs that can eliminate misfolded proteins and reverse the liver disease in model organisms. One of these drugs has advanced to phase II/III clinical trials. The class of drugs may also be utilized for other diseases caused by misfolded proteins, including Alzheimer’s disease and other age-dependent degenerative diseases.

Selected Publications:

Hidvegi T, Ewing M, Hale P, Dippold C, Beckett C, Kemp C, Maurice N, Mukherjee A, Goldbach C, Watkins S, Michalopoulos G, Perlmutter DH. An autophagy-enhancing drug promotes degradation of mutant α1-antitrypsin Z and reduces hepatic fibrosis. Science 2010; 329:229-232. PMID:20522742

Li J, Pak SC, O’Reilly LP, Benson JA, Wang Y, Hidvegi T, Hale P, Dippold C, Ewing M, Silverman GA, Perlmutter DH. Fluphenazine reduces proteototoxicity in C. elegans and mammalian models of α1-antitrypsin deficiency. PLoS One 2014; 9:e87260

Long OS, Benson JA, Kwak J-H, Luke CJ, Gosai SJ, O’Reilly LP, Wang Y, Li J, Vetica AC, Miedel MT, Stolz DB, Watkins SC, Zuchner S, Perlmutter DH, Silverman GA, Pak SC. A C. elegans model of human α1-antitrypsin deficiency links RNAi to misfolded protein turnover. Hum Mol Genet 2014; doi: 10.1093/hmg/ddu235. Epub 2014 May 16. PMID:24838286 PMCID:PMC4159155

O’Reilly LP, Long OS, Cobanoglu MC, Benson JA, Luke CJ, Miedel MT, Hale P, Perlmutter DH, Bahar I, Silverman GA, Pak SC. A genome-wide RNA i screen identifies potential drug targets in a C. elegans model of α1-antitrypsin deficiency. Hum Mol Genet 2014 9(9):1021-32. doi: 10.1517/17460441.2014.930125. Epub 2014 Jul 5. PMID: 2499876

Tafaleng EN, Chakraborty S, Han B, Hale P, Wu W, Soto-Gutierrez A, Feghali-Bostwick CA, Wilson AA, Kotton DN, Nagaya M, Strom SC, Chowdhury JR, Stolz DB, Perlmutter DH, Fox IJ. Induced pluripotent stem cells model personalized variations in liver disease due to α1-antitrypsin deficiency. Hepatology 2015; 62(1):147-57. doi: 10.1002/hep.27753. Epub 2015 Apr 13

Hidvegi T, Stolz DB, Alcorn JF, Yousem SA, Wang J, Leme AS, Houghton AM, Hale P, Ewing M, Cai H, Pastore N, Annunziata P, Kaminski N, Pilewski J, Shapiro SD, Pak SC, Silverman GA, Brunetti-Pierri N, Perlmutter DH. Enhancing autophagy with drugs or lung-directed gene therapy reverses the pathological effects of respiratory epithelial cell proteinopathy. J Biol Chem 2015; 290:29742-29757.

Last Updated: 8/24/2016 4:34:02 PM

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