Gary Silverman

Harriet B Spoehrer Professor of Pediatrics, Head of the Department of Pediatrics, Professor of Genetics, Professor of Cell Biology and Physiology

  • 8752 Citations
1978 …2020

Research output per year

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Personal profile

Research interests

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, a1-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.

Areas of Clinical Interest

newborn medicine, neonatology, perinatal medicine

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Research Output

Functional characterization of four ATP-binding cassette transporter A3 gene (ABCA3) variants

Hu, J. Y., Yang, P., Wegner, D. J., Heins, H. B., Luke, C. J., Li, F., White, F. V., Silverman, G. A., Sessions Cole, F. & Wambach, J. A., Jul 1 2020, In : Human mutation. 41, 7, p. 1298-1307 10 p.

Research output: Contribution to journalArticle

  • Mechanisms of action of autophagy modulators dissected by quantitative systems pharmacology analysis

    Shi, Q., Pei, F., Silverman, G. A., Pak, S. C., Perlmutter, D. H., Liu, B. & Bahar, I., Apr 1 2020, In : International journal of molecular sciences. 21, 8, 2855.

    Research output: Contribution to journalArticle

    Open Access
  • An analog of glibenclamide selectively enhances autophagic degradation of misfolded α1-antitrypsin Z

    Wang, Y., Cobanoglu, M. C., Li, J., Hidvegi, T., Hale, P., Ewing, M., Chu, A. S., Gong, Z., Muzumdar, R., Pak, S. C., Silverman, G. A., Bahar, I. & Perlmutter, D. H., Jan 2019, In : PloS one. 14, 1, e0209748.

    Research output: Contribution to journalArticle

    Open Access
  • 3 Scopus citations

    Autophagy genes in myeloid cells counteract IFNγ-induced TNF-mediated cell death and fatal TNF-induced shock

    Orvedahl, A., McAllaster, M. R., Sansone, A., Dunlap, B. F., Desai, C., Wang, Y. T., Balce, D. R., Luke, C. J., Lee, S., Orchard, R. C., Artyomov, M. N., Handley, S. A., Doench, J. G., Silverman, G. A. & Virgin, H. W., Jan 1 2019, In : Proceedings of the National Academy of Sciences of the United States of America. 116, 33, p. 16497-16506 10 p.

    Research output: Contribution to journalArticle

    Open Access
  • 2 Scopus citations

    CemOrange2 fusions facilitate multifluorophore subcellular imaging in C. Elegans

    Thomas, B. J., Wight, I. E., Chou, W. Y. Y., Moreno, M., Dawson, Z., Homayouni, A., Huang, H., Kim, H., Jia, H., Buland, J. R., Wambach, J. A., Cole, F. S., Pak, S. C., Silverman, G. A. & Luke, C. J., Mar 2019, In : PloS one. 14, 3, e0214257.

    Research output: Contribution to journalArticle

    Open Access
  • 2 Scopus citations