Judy Lieberman’s laboratory studies cytotoxic T lymphocytes (CTLs) and their role in antiviral immunity. It focuses on the molecular pathways used by CTLs to induce cell death, especially the CTL protease granzyme A, which induces a novel form of programmed cell death. Several novel protein substrates of granzyme A have been identified. The lab is working out the molecular basis for DNA destruction and mitochondrial damage in this caspase-independent apoptotic pathway. The lab has shown that granzyme A targets the SET complex, a chromatin modifying and DNA repair complex mobilized in response to oxidative stress, which contains the granzyme A-activated DNase. One goal is to understand the normal function of the SET complex in cells. Recent work is also aimed at understanding the biochemistry and cell biology behind the action of perforin, the CTL protein responsible for delivering the death-inducing granzymes into targeted cells.
The Lieberman lab was the first to demonstrate that RNA interference (RNAi) could be harnessed to protect animals from disease. Her laboratory is currently working to translate RNAi for therapeutic use for HIV and other indications. They recently showed that siRNAs could be used as the active ingredient of a topical microbicide to protect mice from vaginal exposure to lethal herpes simplex virus type-2 in mice and are working to develop RNAi based microbicides for prevention of human HIV and HSV-2 transmission. The lab is also investigating the role of microRNAs in HIV infection and cell differentiation and the role of novel host factors in the HIV life cycle.
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References:
Song E, Zhu P, Lee S-K, Chowdhury D, Kussman S, Dykxhoorn DM, Feng Y, Palliser D, Weiner DB, Shankar P, Marasco WA and Lieberman J. Antibody-mediated delivery of small interfering RNAs via cell surface receptors. Nature Biotech 2005; 9:347-351.
Chowdhury D, Beresford PJ, Zhu P, Zhang D, Sung J-S, Demple B, Perrino F and Lieberman J. The exonuclease TREX1 is in the SET complex and acts in concert with NM23-H1 to degrade DNA during granzyme A-mediated cell death. Mol Cell 2006; 23:133-142.
Palliser D, Chowdhury D, Wang, Q-Y, Lee SJ, Bronson RT, Knipe DM, and Lieberman J. An siRNA-based microbicide protects mice from lethal herpes simplex virus 2 infection. Nature 2006; 439:89-94.
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.
Brass AL, Dykxhoorn DM, Benita Y, Yan N, Engelman A, Xavier RJ, Lieberman J and Elledge SJ. Identification of Host Proteins Required for HIV Through a Functional Genomic Screen. Science 2008; 319:921-926.
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.
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