The Lieberman laboratory studies cytotoxic T lymphocytes, key cells in the immune defense against viral infection and cancer, and their role in antiviral immunity.
Cytotoxic T lymphocytes (CTL) recognize and destroy virally infected or cancerous cells. A major focus of the Lieberman laboratory is studying the molecular pathways used by CTLs to induce cell death. Granzyme A, the most abundant CTL death-inducing protease, induces a novel form of programmed cell death that is caspase-independent. Many tumors and viruses resistant to the classical pathway of cell death are sensitive to Granzyme A. The Lieberman laboratory has identified several novel protein substrates of granzyme A, worked out the molecular basis for DNA destruction, and identified a novel mitochondrial cell death pathway activated by granzyme A. One of the main targets of granzyme A is a chormatin -modifying complex (the SET complex) mobilized in response to oxidative stress. The laboratory is working to understand the functions of this complex in modifying chromatin and repairing DNA damage. The laboratory is also seeking to understand how perforin delivers granzymes to target cells.
Other work centers on understanding how the function of cytotoxic T lymphocytes is regulated. Her laboratory is particularly interested in characterizing the cytotoxic T lymphocyte response to HIV-1, the virus that causes AIDS, and why it does not ultimately control the virus. They have found that although there are a large number of HIV-specific T cells in HIV-infected individuals, their function is significantly compromised in vivo. They have linked this functional defect to down-modulation of key signaling molecules, such as CD3zeta and CD28, and to lack of expression of perforin. Knowledge gained from laboratory studies is used to develop and test in small clinical studies immune-based therapeutic and preventive strategies to treat HIV-infection. Currently her laboratory is working to develop an oral HIV vaccine using a Listeria monocytogenes vector.
Her interest in HIV led to recent work to harness RNA interference (RNAi) as a therapeutic tool. Her laboratory was able to harness this ancient antiviral defense mechanism, originally described in plants and worms, but more recently in mammalian cells, to suppress HIV infection. More recently she was the first to demonstrate in an animal model that RNAi could be used to protect animals from disease. Her laboratory is currently actively working on translating RNAi for therapeutic use for HIV and other indications.
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Papers & Publications:
D Martinvalet, P Zhu and J Lieberman. Granzyme A induces caspase-independent mitochondrial damage, a required first step for apoptosis. Immunity 22:355-370, 2005.
E Song, P Zhu, S-K Lee, D Chowdhury, S Kussman, DM Dykxhoorn, Y Feng, D Palliser, DB Weiner, P Shankar, WA Marasco and J Lieberman. Antibody-mediated delivery of small interfering RNAs via cell surface receptors. Nature Biotech 9:347-351, 2005.
E Song, SK Lee, J Wang, N Ince, N Ouyang, J Min, J Chen, P Shankar, and J Lieberman, RNA interference targeting fas protects mice from fulminant hepatitis, Nature Med 9:347-351, 2003.
Z Fan, PJ Beresford, DY Oh, D Zhang, J Lieberman, Tumor suppressor NM23-H1 is a granzyme A-activated DNase during CTL mediated apoptosis, and the nucleosome assembly protein SET is its inhibitor, Cell 112:659-672, 2003.
J Lieberman, Cell death and immunity: The ABCs of granule-mediated cytotoxicity: new weapons in the arsenal, Nat Rev Immunol 3:361-70, 2003. |
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