Judy Lieberman, MD, PhD
|Hospital Title||Senior Investigator, Immune Disease Institute and Program in Cellular and Molecular Medicine|
|Academic Title||Professor of Pediatrics|
Immune Disease Institute
Harvard Medical School Warren Alpert Building, Room 255
200 Longwood Ave
Boston, MA 02115
The Lieberman laboratory studies the molecular pathways used by cytotoxic T cells and natural killer cells to induce death of virus infected cells or tumors. They have defined a novel form of programmed cell death induced by the most abundant cytotoxic granule serine protease, granzyme A. This caspase-independent cell death pathway has all the morphological features of apoptosis but involves single-stranded DNA damage, not double stranded DNA breaks. It does not involve caspase activation or share substrates with the caspases, and cells that are resistant to the caspase pathway, such as by overexpressing bcl-2, are sensitive to granzyme A. Granzyme A activates a novel form of mitochondrial damage without cytochrome c release. A special target of this cell death pathway is an oxidative stress response complex, called the SET complex, which contains DNA repair enzymes and proteins involved in chromatin modification and transcriptional activation in response to oxidative stress. A key focus is to understand the normal function of the SET complex and its potential role in cellular transformation and the response to stress and DNA damage. Recent work is also aimed at understanding the biochemical and cell biological basis for the function of perforin, the membrane-perturbing protein that delivers the CTL granzyme proteases into cells. The Lieberman laboratory also studies how CTL function is regulated in the setting of chronic infection, with a particular emphasis on HIV infection.
The Lieberman laboratory was the first to demonstrate in an animal model that RNA interference (RNAi) could be used to protect animals from disease. Her laboratory is actively working to harness RNAi for therapeutic use for HIV and other indications and has developed novel strategies for cell-specific targeting of small interfering RNAs that are effective in vivo. The lab is also investigating the role of the endogenous microRNA pathway in hematopoietic cell differentiation, cellular transformation and viral infection.
About Judy Lieberman
Dr. Lieberman received a PhD from Rockefeller University and an MD in the Harvard-MIT Program in Health, Science and Technology. She completed a residency and heme-onc fellowship at Tufts-New England Medical Center and a postdoctoral fellowship in immunology at MIT.
Yu F, Yao H, Zhu P, Zhang X, Pan Q, Gong C, Huang Y, Hu X, Su F, Lieberman J* and Song E*. let-7 regulates self-renewal and tumorigenicity of breast cancer cells. Cell 2007; 131:1109-1123.
Martinvalet D, Dykxhoorn DM, Ferrini R and Lieberman J. Granzyme A cleaves a mitochondrial complex I protein to initiate caspase independent cell death. Cell 2008; 133:681-692.
Yan N, Regalado-Magdos, AD, Stiggelbout B, Lee-Kirsch MA and Lieberman J. The cytosolic exonuclease TREX1 inhibits the innate immune response to human immunodeficiency virus type 1. Nature Immunol 2010; 11:1005-1013.
Wheeler LA, Trifonova R, Vrbanac V, Basar E, McKernan S, Xu Z, Seung E, Deruaz M, Dudek T, Einarsson JI, Yang L, Allen TM, Luster AD, Tager AM, Dykxhoorn DM and Lieberman J. CD4 aptamer-siRNA chimeras inhibit sexual transmission of HIV to human cervicovaginal explants and humanized mice. J Clin Invest 2011; 121:2401-2412.
- Thiery J, Keefe D, Boulant S, Boucrot E, Walch M, Martinvalet D, Goping IS, Bleackley RC, Kirchhausen T and Lieberman J. Perforin pores in the endosomal membrane trigger release of granzyme B to the cytosol of target cells. Nature Immunol 2011; 12:770-777.