Charleen T. Chu, M.D. Ph.D.
Associate Professor, Pathology- M.D. Duke University (1994)
- Ph.D. Duke University (1993)
- Office: W958 Biomedical Science Tower
- Telephone:412-383-5379
- Fax:412-647-5602
- E-mail: ctc4@pitt.edu
- Website: http://path.upmc.edu/personnel/Faculty/Chu.htm
Redox cell signaling and autophagy in neuroprotection and neurodegeneration.
Research Summary:
Dr. Chu’s research focuses on cellular and molecular mechanisms relevant to parkinsonian neurodegenerative diseases and chemical neurotoxins. Specifically, her research team explores the interplay between oxidative stress, cell signaling and neuronal survival/death decisions.
Reactive oxygen species and mitochondrial pathobiology have been implicated in the pathogenesis of neurotoxin and genetic models of Parkinson's disease (PD). Although the extracellular signal regulated protein kinases (ERK) are activated by trophic factors, redox activation of this signaling pathway promotes neuronal cell death. Our studies in primary neurons and neuronal cell lines, in conjunction with examination of diseased human brain tissues, suggest that deranged trafficking and transport of signaling proteins contributes to neurite degeneration and cell death. Despite robust activation of neuroprotective signaling cascades, neuroprotective nuclear transcription is reduced. Moreover, sustained cytoplasmic and mitochondrial ERK activation contribute actively to neuronal injury, potentially through regulation of autophagy.
Areas of current emphasis include the following: What are the redox mechanisms that result in decreased nuclear trafficking of signaling proteins. How is pathologically activated ERK targeted to mitochondria, and what are the downstream consequences of mitochondrial ERK signaling? What is the role and regulation of autophagy during neurite remodeling and autophagic cell death. Finally, gene-environment interactions are important to parkinsonian pathogenesis. New directions in the lab incorporate chemical exposures with the study of kinases that are mutated in familial PD -- PINK1 and LRRK2. The long-term goals are to employ our understanding of mechanisms by which adaptive responses are dysregulated during acute and chronic neurodegenerative stresses in order to develop neuroprotective or regenerative therapies.
Trainees in the laboratory will be exposed to biochemical, immunochemical, image analysis, and molecular techniques as applied to cell culture and transgenic/neurotoxic mouse models. In addition, we conduct multi-label neuropathologic and biochemical studies of diseased tissues from patients with PD, Lewy body dementia (LBD), and progressive supranuclear palsy (PSP), a parkinsonian tauopathy. The ability to test predictions in post-mortem human neurodegenerative disease brain samples has twice translated to new directions for our experimental work.
Selected Publications:
Dagda, R.K., Zhu, J., Kulich, S.M. and Chu, C.T. Mitochondrially localized ERK2 regulates mitophagy and autophagic cell stress. Autophagy, 4: 770-782, 2008.
Cherra III, S.J. and Chu, C.T. Autophagy in neuroprotection and neurodegeneration: a question of balance (review). Future Neurol, 3: 309-323, 2008.
Plowey, E.D., Cherra III, S.J., Liu, Y-J. and Chu, C.T. Role of autophagy in G2019S-LRRK2-associated neurite shortening in differentiated SH-SY5Y cells. J Neurochem, 105: 1048-1056, 2008.
Chu, C.T., Plowey, E., Wang, Y., Patel, V. and Jordan-Scuitto, K.L. Location, location, location: Altered transcription factor trafficking in neurodegeneration (review). J Neuropath Exp Neurol, 66: 873-883, 2007.
Zhu, J.H., Horbinski, C., Guo, F., Watkins, S., Y Uchiyama, Y. and Chu, C.T. Regulation of autophagy by extracellular signal regulated protein kinases during 1-methyl-4-phenylpyridinium injury. Am J. Pathol, 170: 75-86, 2007.
Chalovich, E.M., Zhu, J.H., Caltagarone, J., Bowser, R. and Chu, C.T. Functional repression of cAMP response element in 6-hydroxydopamine-treated neuronal cells. J. Biol. Chem, 281: 17870-17881, 2006.
Link to a more complete list of Dr. Chu’s recent publications