Gary A. Silverman, M.D., Ph.D.

Harriet B Spoehrer Professor and Chair

Biochemistry, Biophysics, and Structural Biology Program
Developmental, Regenerative and Stem Cell Biology Program
Molecular Cell Biology Program
Molecular Genetics and Genomics Program

  • 314-454-6005

  • 314-454-0537

  • 8116

  • McDonnell Pediatric Research Building 4108 & 4110



  • serpins, cell death, lysosomes, necrotizing enterocolitis, C. elegans, proteases, protein misfolding, alpha-1 antitrypsin deficiency, drug discovery

  • The cellular response to life threatening human diseases.

Research Abstract:

Life threatening human diseases drastically alter cellular homeostasis triggering cellular dysfunction, tissue damage, and death. Proteases are the major executioners of cell death, and are blocked, in part, by endogenous inhibitors such as serpins. Our laboratory focuses on the interplay between cell stress (e.g., infection, hypoxia, hyperoxia, and electrolyte disturbances), protease activation, and serpin blockade. Using multiple technologies (e.g., live-cell imaging, chemical mutagenesis, RNAi, and CRISPR/Cas9) in C. elegans, mouse, and cell culture models of human diseases, we show that serpins serve as pro-survival factors. Certain serpins neutralize lysosomal cysteine proteases, and block a novel form of regulated cell death, lysosomal-mediated necrosis. This cell death pathway is activated after major cellular insults as occurs in newborns with necrotizing enterocolitis or after severe bacterial infections. We are further defining the genetic and molecular basis of this pathway, and are searching for compounds that inhibit this form of cell death.

Interestingly, however, serpins are metastable proteins and some mutations in serpin genes lead to the synthesis of misfolded, aggregation-prone proteins that induce cellular stress themselves. These conformational diseases, called serpinopathies (a subset of the proteinopathies or conformational diseases), perturb proteostasis and induce cellular injury. The canonical serpinopathy, alpha-1-antitrypsin (AT) deficiency (ATD), results in the aggregation and retention of AT in the ER of liver cells where it causes inflammation, cirrhosis, and hepatocellular carcinoma. ATD is a prototype for other conformational diseases such as Alzheimer’s, Huntington’s, and Parkinson’s diseases, but is unique in that the misfolded proteins are retained in the ER. Since there are no known cures for these conformational disorders, we tested the feasibility of modeling ATD in C. elegans, and using this powerful genetic system to conduct high-throughput drug and genetic screens to search for hit compounds and modifier genes that serve as new therapeutic targets, respectively. This semi-automated, highly reproducible, live-animal, high throughput drug discovery platform rivals that of any cell-based system. Early findings of this pre-clinical work show that FDA-approved drugs can be re-purposed and used to reduce ATZ accumulation and cellular toxicity by enhancing autophagy.

Selected Publications:

Niehaus JZ, Miedel MT, Good M, Wyatt AN, Pak SC, Silverman GA, Luke CJ. SERPINB12 Is a Slow-Binding Inhibitor of Granzyme A and Hepsin. Biochemistry. 2015 Nov 17;54(45):6756-9. Epub 2015 Nov 5. PMID: 26497600

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 Dec 11;290(50):29742-57. PMID: 26494620 [COVER ILLUSTRATION]

Silverman RM, Cummings EE, O`Reilly LP, Miedel MT, Silverman GA, Luke CJ, Perlmutter DH, Pak SC. The aggregation-prone intracellular serpin SRP-2 fails to transit the ER in Caenorhabditis elegans. Genetics. 2015 May;200(1):207-19. doi: 10.1534/genetics.115.176180. Epub 2015 Mar 18. PMID: 25786854

Niehaus JZ, Good M, Jackson LE, Ozolek JA, Silverman GA, Luke CJ. Human SERPINB12 Is an Abundant Intracellular Serpin Expressed in Most Surface and Glandular Epithelia. J Histochem Cytochem. 2015 Nov;63(11):854-65. Epub 2015 Jul 28. PMID: 26220980. [COVER ILLUSTRATION]

O’Reilly LP, Long O, Cobanoglu MC, Benson JA, Miedel MT, King DE, Bahar I, Perlmutter DH, Silverman GA, Pak SC. A genome-wide RNAi screen identifies potential drug targets in a C. elegans model of α1-anitrypsin deficiency. Hum Mol Genet. 2014. Oct 1;23(19):5123-32. Epub 2014 May 16. PMID: 24838285; PMCID: PMC4159156

Long OS, Benson JA, Kwak JH, 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 components of the RNAi pathway to misfolded protein turnover. Hum Mol Genet. 2014. Oct 1;23(19):5109-22. Epub 2014 May 16. PMID: 24838286; PMCID: PMC4159155

Luke CJ, Pak SC, Askew YS, Naviglia TL, Askew DJ, Nobar SM, Vetica AC, Long OS, Watkins SC, Stolz DB, Barstead RJ, Moulder GL, Bromme D, Silverman GA. An intracellular serpin regulates necrosis by inhibiting the induction and sequelae of Lysosomal injury. Cell. 2007 Sep 21;130(6):1108-1119. PMID: 17889653; PMCID: PMC2128786 [COVER ILLUSTRATION]

Last Updated: 3/30/2017 11:44:57 AM

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