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J. Marie Hardwick, PhD

Department Affiliations Department of Molecular Microbiology and Immunology Departments of Neurology, Pharmacology and Molecular Sciences, Oncology, Biochemistry and Molecular Biology
Rank David Bodian Professor
Office Phone 410-955-2716 Office/ 410-614-3130 Assistant
Lab Phone
Fax 410-955-0105
Email hardwick@jhu.edu
SOM Address E5140 Bloomberg School of Public Health Building
Website
Students

Heidi Galonek 1998 – 2005

Nicole Zadzilka 2004 – 2007

Research Interests

Programmed cell death is an essential process for eliminating cells during development, tissue remodeling and virus infections. Defects in the programmed cell death pathways lead to a variety of disease states. For example, insufficient cell death underlies the development and progression of cancer, while excessive cell death is responsible for a variety of neurological and other disease states. Our lab studies the basic molecular mechanisms of programmed cell death using cultured cell lines, neurons, mice, virus infections and yeast genetics. We have shown that viruses can trigger cells to activate a cellular apoptotic death pathway (Nature, 361:739-742, 1993). Virus-induced apoptotic cell death can be either a host defense mechanism or result in a disease state (J. Virol. 70:1828-1835, 1996; PNAS 94: 690-694, 1997). We also use viruses as tools to explore cellular pathways. Our Sindbis virus vector delivers genes of interest to a variety of cultured cell types and to neurons in mouse bains, facilitating the study and characterization of both cellular and viral regulators of apoptosis. (Nature 379:554-556, 1996; PNAS 93:4810-4815, 1996). This strategy has yielded some surprising findings about cellular and viral mechanisms of apoptosis (EMBO J. 15:2685-2694, 1996; J. Virol. 71:4118-4122, 1997; J. Virol. 72:327-338, 1998). For example, the Bax and Bak proteins are known to be potent pro-apoptotic members of the Bcl-2 family, but we found that these proteins potently protect neurons in culture and in mouse brains (Nature Med. 5:832-835, 1999) in part by regulating neuron excitability (Dev Cell, 4:575-585, 2003). Conversely, the anti-apoptotic Bcl-2 and Bcl-xL proteins can be converted into pro-death molecules (Science 278:1966-1968, 1997; Proc. Natl. Acad. Sci. 95:554-559, 1998). The Sindbis virus vector has also allowed us to demonstrate that the genetic mutations in patients with spinal muscular atrophy convert an anti-apoptotic SMN protein into a killer protein (Proc. Natl. Acad. Sci USA 97:13312-13317, 2000). The mechanisms by which Bcl-2 family proteins, viral Bcl-2 homologues and their binding partners, regulators of mitochondrial morphology and function and other modulators of cell survival/death are currently under study (Molec. Cell 6:31-40, 2000; J. Virol. 74:5024-5031, 2000, J. Biol. Chem. 276:31083-31091, 2001). These and other findings in our laboratory have led to new hypothesis about the “day jobs” versus “dark alley tricks” of cell death regulators.

Publications

Research Profile

  • Fannjiang, Y., Kim, C.-H., R.L.Huganir, R.L., Zou, S., Lindsten, T., Thompson, C.B., Mito, T., Traystman, R.J., Larsen, T., Griffin, D.E., Mandir, A.S., Dawson, T.M., Dike, S., Sappington, A.L., Kerr, D.A., Jonas, E.A., Kaczmarek, L.K., & Hardwick, J.M. 2003. BAK alters neuronal excitability and can switch from anti- to pro-death function during postnatal development. Develop. Cell 4:575-585.
  • Jonas, EA, Hickman, JA, Chachar, M, Polster, BM, Fannjiang, Y, Basanez, G, Kinnally, KW, Zimmerberg, J, Hardwick, JM*, Kaczmarek, LK* 2004. Proapoptotic N-truncated BCL-xL activates endogenous mitochon-drial channels in living synaptic terminals. Proc. Natl. Acad. Sci. USA 101:13590-5. *co-corresponding
  • Seo, S. Y., Chen, Y.-b., Ivanovska, I., Ranger, A. M., Hong, S. J., Dawson, V. L., Korsmeyer, S. J., Bellows, D.S. Fannjiang, Y. and Hardwick, J.M. 2004. Caspase cleavage converts BAD from an anti-apoptotic to a pro-apoptotic factor. J. Biol. Chem. 279:42240-42249.
  • Fannjiang, Y.*, Cheng, W.-C.*, Lee, S.J., Qi, B, Pevsner, J., McCaffery, J.M., Hill R.B., Basaez G., and Hardwick J.M. 2004. Mitochondrial fission proteins regulate programmed cell death in yeast. Genes & Dev 18:2785-2797. *co-contributors
  • Hardwick, J.M. and Cheng, W.C. 2004 Mitochondrial programmed cell death pathways in yeast. Devel. Cell 7:630-632. (short review)