The main objective of this proposal is to investigate neurotoxicities caused by translational protein complex aggregation after brain ischemia. An episode of brain ischemia leads to delayed neuronal death at 72 hours of reperfusion. We have recently found that brain ischemia causes aggregation of translational complex, i.e., ribosomes and ribosome-associated proteins, thus demolishing protein synthesis machinery in ischemic vulnerable neurons. 4 lines of evidence strongly suggest that destruction of protein synthesis machinery by aggregation plays a causative role in delayed neuronal death after brain ischemia: (1) Translational complex aggregation is seen as early as 2 hours, and is progressively accumulated in neurons until their death at about 72 hours of reperfusion; (2) Translational complex aggregation occurs only in brain regions where neurons are destined to die, but does not take place in brain areas where neurons survive the same ischemic insult, suggesting that translational complex aggregation may not be an epiphenomenon; (3) All measures that prevent translational complex aggregation enhance resistance of neurons to ischemia; (4) Protein synthesis is irreversibly destroyed by translational complex aggregation in vulnerable neurons after ischemia. Based on these observations, we propose a new hypothesis for delayed neuronal death after ischemia whereby the ischemia-induced cascade of energy failure, disabilities of protein chaperoning and protein degradation cumulatively cause translational complex aggregation, thus destroying protein synthesis machinery. Such destruction of protein synthesis machinery accumulates over time, and ultimately leads to delayed neuronal death after brain ischemia. Can translational complex aggregation be prevented? The answer should be positive, provided that the molecular mechanisms are understood. The objective of this proposal is to study molecular mechanisms of translational complex aggregation after brain ischemia.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-BDCN-L (90))
Program Officer
Jacobs, Tom P
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Miami School of Medicine
Schools of Medicine
Coral Gables
United States
Zip Code
Yuan, Dong; Liu, Chunli; Wu, Jiang et al. (2018) Inactivation of NSF ATPase Leads to Cathepsin B Release After Transient Cerebral Ischemia. Transl Stroke Res 9:201-213
Yuan, Dong; Liu, Chunli; Hu, Bingren (2018) Dysfunction of Membrane Trafficking Leads to Ischemia-Reperfusion Injury After Transient Cerebral Ischemia. Transl Stroke Res 9:215-222
Sun, Xin; Crawford, Robert; Liu, Chunli et al. (2015) Development-dependent regulation of molecular chaperones after hypoxia-ischemia. Neurobiol Dis 82:123-131
Park, Yujung; Liu, Chunli; Luo, Tianfei et al. (2015) Chaperone-Mediated Autophagy after Traumatic Brain Injury. J Neurotrauma 32:1449-57
Luo, Tianfei; Roman, Philip; Liu, Chunli et al. (2015) Upregulation of the GEF-H1 pathway after transient cerebral ischemia. Exp Neurol 263:306-13
Sabirzhanova, Inna; Liu, Chunli; Zhao, Jingwei et al. (2013) Changes in the GEF-H1 pathways after traumatic brain injury. J Neurotrauma 30:1449-56
Zhang, Fan; Guo, Ailan; Liu, Chunli et al. (2013) Phosphorylation and assembly of glutamate receptors after brain ischemia. Stroke 44:170-6
Degracia, Donald; Hu, Bingren (2013) Protein misfolding and organelle stress after brain ischemia. Transl Stroke Res 4:579-80
Luo, Tianfei; Park, Yujung; Sun, Xin et al. (2013) Protein misfolding, aggregation, and autophagy after brain ischemia. Transl Stroke Res 4:581-8
Kristian, Tibor; Hu, Bingren (2013) Guidelines for using mouse global cerebral ischemia models. Transl Stroke Res 4:343-50

Showing the most recent 10 out of 25 publications