Department Affiliation: Primary: Molecular Microbiology and Immunology, Secondary: Neurology; Pharmacology and Molecular Sciences; Biochemistry and Molecular Biology; Oncology
Degree: Ph.D., University of Kansas
Rank: The David Bodian Professor
Telephone Number: 410-955-2716
Fax Number: 410-955-0105
E-mail address: hardwick@jhu.edu
School of Medicine Address: Room E5140, Bloomberg Public Health Bldg., 615 N. Wolfe St., Baltimore, MD 21205
Molecular mechanisms of programmed cell death
Our research is focused on understanding the basic mechanisms of programmed cell death and their role in disease pathogenesis. Every day, millions of cells die in the human body by a purposeful suicide pathway. Although cell growth and differentiation are critical for normal development and health, we suggest that perhaps all cancers arise from a defect in one of many genetically programmed cell suicide pathways, and that neuronal malfunction and loss during aging and various disease states is due to inappropriate activation of the suicide program. We have reported that many insults, including viruses, trigger cells to activate a cellular death pathway (Nature, 361:739-742, 1993), that many oncogenic viruses encode proteins to block attempted cell suicide (Proc. Natl. Acad. Sci. 94: 690-694, 1997), that cellular anti-death genes can alter the pathogenesis of virus infections (Nature Med. 5:832-835, 1999), of genetic diseases (Proc. Natl. Acad. Sci. 97:13312-7, 2000) and of many other human disorders. However, the detailed molecular and biochemical mechanisms by which the Bcl-2 oncogene, neuronal SMN, lymphocyte IAP proteins and most other viral and cellular factors modulate cell death/survival are largely unknown. Furthermore, we think that cell death inhibitors are also regulators of basic cellular functions, including mitochondrial bioenergetics, and that cellular anti-death factors can be converted into pro-death molecules, providing potential strategies for treating cancer (Science 278:1966-8, 1997; Molec. Cell 6:31-40, 2000). In addition, we have delineated important differences between viral and cellular homologues of apoptosis regulators (J. Virol. 74:5024-31, 2000; J. Virol. 76:2469-79, 2002).
Current projects in the Hardwick laboratory include:
- Bcl-2 family proteins. The molecular, biophysical and physiological differences between human Bcl-2 proteins and their tricky viral homologues.
- Mitochondria and cell energetics. The Hardwick laboratory suggests that killer proteins harbored inside healthy cells are not just "latent" death factors waiting to kill cells, but rather have “day jobs” in essential biochemical processes (e.g. metabolism, neuronal activity, mitochondrial structure), and are only converted into killing factors should the occasion arise.
- Yeast genetics and bioinformatics. While programmed cell death is known to be essential for sculpting bodies and preventing cancer, we think that programmed cell death is an ancient and fundamental process conserved even in unicellular organisms such as yeast, for which there are highly sophisticated research tools available to probe the molecular mechanisms of programmed cell death.
- Cellular mechanisms that allow mosquito-borne encephalitis viruses to induce programmed cell death in mammalian neurons but not in mosquitoes.
Neurogenesis and neuronal death in spinal cord disease.
Representative Publications:
- Fannjiang, Y., Kim, C.H., 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., and Hardwick, J.M. BAK alters neuronal excitability and can switch from anti- to pro-death function during postnatal development, Dev. Cell. 4:575-585. 2003. Pub Med Reference
- Hardwick, J.M., Polster, B.M. Bax, along with lipid conspirators, allows cytochrome c to escape mitochondria, Mol. Cell. 10:963-965. 2002. Pub Med Reference
- Jonas, E..A., Hoit, D., Hickman, J.A., Brandt, T.A., Polster, B.M., Fannjiang, Y., McCarthy, E., Montanez, M.K., Hardwick, J.M., and Kaczmarek, L.K. Modulation of synaptic transmission by the BCL-2 family protein BCL-xL, J. Neuroscience 23:8423-8431, 2003. (See Commentary, same issue). Pub Med Reference
- Jonas, E.A., Hickman, J.A., Chachar, M., Polster, B.M., Fannjiang, Y., Basanez, G., Kinnally, K.W., Zimmerberg, J., Hardwick, J.M.*, and Kaczmarek, L.K.* Proapoptotic N-truncated BCL-xL activates endogenous mitochondrial channels in living synaptic terminals, Proc. Natl. Acad. Sci. USA 101:13590-5. 2004. (*co-corresponding) Pub Med Reference
- 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. Caspase cleavage converts BAD from an antiapoptotic to a proapoptotic factor, J. Biol. Chem. 279:42240-42249. 2004. Pub Med Reference
- Fannjiang, Y., Cheng, W.-C., Lee, S.J., Qi, B., Pevsner, J., McCaffery, J.M., Hill, R.B., Basañez, G., and Hardwick, J.M. Mitochondrial fission proteins regulate programmed cell death in yeast, Genes & Dev. 18:2785-2797. 2004. Pub Med Reference
- Hardwick, J.M. and Chang, W.C. Mitochondrial programmed cell death pathways in yeast, Dev. Cell 7:630-632, 2004. Pub Med Reference
- Ivanovska, I. and Hardwick, J.M. Viruses activate a genetically conserved cell death pathway in a unicellular organism, J. Cell Biol. 170:391-399, 2005. (Reviewed in Aug. 9, AAAS Science STKE 296:287, 2005.) Pub Med Reference
BCMB Program
Cellular and Molecular Medicine Graduate Program
Biochemistry and Molecular Biology Program (School of Public Health)
Molecular Microbiology and Immunology Program (School of Public Health)
