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School of Medicine
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J. Marie Hardwick
Department Affiliation: Primary: Molecular Microbiology and Immunology;
Joint: Pharmacology and Molecular Sciences
Secondary: Neurology; 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: firstname.lastname@example.org
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 in disease pathogenesis. Billions of cells die per day in the human body. Like cell division and differentiation, cell death is also critical for normal development and maintenance of healthy tissues. Apoptosis and other forms of cell death are required for trimming excess, expired and damaged cells. Therefore, many genetically programmed cell suicide pathways have evolved to promote long-term survival of species from yeast to humans. Defective cell death programs cause disease states. Insufficient cell death underlies human cancer and autoimmune disease, while excessive cell death underlies human neurological disorders and aging. Of particular interest to our group are the mechanisms by which Bcl-2 family proteins and other factors regulate programmed cell death, particularly in the nervous system, in cancer and in virus infections. Interestingly, cell death regulators also regulate many other cellular processes prior to a death stimulus, including neuronal activity, mitochondrial dynamics and energetics. We study these unknown mechanisms.
We have reported that many insults can trigger cells to activate a cellular death pathway (Nature, 361:739-742, 1993), that several 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) and of genetic diseases (PNAS. 97:13312-7, 2000) reflective of many human disorders. We have shown that anti-apoptotic Bcl-2 family proteins can be converted into killer molecules (Science 278:1966-8, 1997), that Bcl-2 family proteins interact with regulators of caspases and regulators of cell cycle check point activation (Molecular Cell 6:31-40, 2000). In addition, Bcl-2 family proteins have normal physiological roles in regulating mitochondrial fission/fusion and mitochondrial energetics to facilitate neuronal activity in healthy brains.
Current projects in the Hardwick laboratory include:
* Bcl-2 family proteins. Understudy are the detailed molecular and biochemical mechanisms by which the Bcl-2 family proteins and their associated factors regulate cell death. Also of interest are the mechanisms that viral Bcl-2 proteins use to escape normal cellular control mechanisms and the functions they provide to a diverse group of viruses.
* Mitochondria and cell energetics. We think that apoptosis regulators have additional functions in healthy cells and are not simply "latent" death factors waiting to kill cells, but can be converted into killing factors should the occasion arise. We are investigating these “day jobs” of apoptosis regulators, such as metabolism, neuronal activity, mitochondrial structure.
* Yeast genetics and bioinformatics. While programmed cell death is 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. We have developed new tools to tap this powerful system to study programmed cell death in yeast, particularly in those processes related to the earliest phases of human tumorigenesis.
* Cellular mechanisms that allow mosquito-borne encephalitis viruses to induce programmed cell death in mammalian neurons but not in mosquitoes.
- 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
- Galonek, H.L. and Hardwick, J.M. 2006. Upgrading the BCL-2 network. Nature Cell Biology 8: 1317-1319. Pub Med Reference
- Cheng, W.C., Teng, X., Park, H.K., Tucker, C.M., Dunham, M.J., Hardwick, J.M. 2008. Fis1 deficiency selects for compensatory mutations responsible for cell death and growth control defects. Cell Death Differ (Nature) 15:1838-1846. Pub Med Reference
- Berman, S.B., Chen, Y.B., Qi, B., McCaffery, J.M., Rucker, E.B. 3rd, Goebbels, S., Nave, K.A., Arnold, B.A., Jonas, E.A., Pineda, F.J., and Hardwick, J.M. 2009. Bcl-xL increases mitochondrial fission, fusion, and Biomass in neurons. J Cell Biol. 184:707-719. Pub Med Reference
- Hardwick, J.M. and Youle, R.J. 2009. SnapShot: BCL-2 proteins. Cell 138:404-405. Pub Med Reference
- Teng, X. and Hardwick, J.M. 2010. The apoptosome at high resolution. Cell 141(3):402-4. Pub Med Reference
- Hartman, A.L., Zheng, X., Bergbower, E., Kennedy, M., Hardwick, J.M. 2010. Seizure tests distinguish intermittent fasting from the ketogenic diet. Epilepsia 51(8):1395-402. Pub Med Reference
- Teng, X., Cheng, W.C., Qi, B., Yu, T.X., Ramachandran, K., Boersma, M.D., Hattier, T., Lehmann, P.V., Pineda, F.J., Hardwick, J.M. 2011. Gene-dependent cell death in yeast. Cell Death & Disease 2:e188. Pub Med Reference
- Alavian, K.N., Li, H., Collis, L., Bonanni, L., Zeng, L., Sacchetti, S., Lazrove, E., Nabili, P., Flaherty, B., Graham, M., Chen, Y., Messerli, S.M., Mariggio, M.A., Rahner, C., McNay, E., Shore, G.C., Smith, P.J., Hardwick, J.M., Jonas, E.A. 2011. Bcl-xL regulates metabolic efficiency of neurons through interaction with the mitochondrial F1FO ATP synthase. Nat. Cell Biol. 13(10):1224-33. Pub Med Reference
- Chen, Y.B., Aon, M.A., Hsu, Y.T., Soane, L., Teng, X., McCaffery, J.M., Cheng, W.C., Qi, B., Li, H., Alavian, K.N., Dayhoff-Brannigan, M., Zou, S., Pineda, F.J., O'Rourke, B., Ko, Y.H., Pedersen, P.L., Kaczmarek, L.K., Jonas, E.A., Hardwick, J.M. 2011. Bcl-xL regulates mitochondrial energetics by stabilizing the inner membrane potential. J. Cell Biol. 195(2):263-76. Pub Med Reference
Other graduate programs in which Dr. Hardwick participates: