The main objective of this project is to investigate the toxicity of protein aggregates formed in postischemic neurons. A short period of cerebral ischemia causes delayed neuronal death at about 3 days of reperfusion in hippocampal CA1 pyramidal neurons while leaving dentate gyrus neurons largely intact. We have recently obtained strong biochemical and morphological evidence that ischemia causes dramatic and progressive accumulation of protein aggregates in neurons prior to their death and that these aggregates are virtually absent in the neurons that survive the insult. The most marked accumulation of protein aggregates was found on the membranes of intracellular vesicles, the endoplasmic reticulum (ER), mitochondria and the dendritic plasmalemma. Induction of molecular chaperones in neurons by transgenic overexpression or ischemic preconditioning prevented both protein aggregate formation and ischemic neuronal death. Based on these results, we propose a new hypothesis for ischemic cell death whereby overproduction of unfolded proteins after ischemia causes formation of irreversible protein aggregates that ultimately lead to delayed neuronal death.
The specific Aims are: (i). To characterize further protein aggregation after ischemia and its relationship to cell death by confocal microscopy, quantitative EM analysis and EM tomography. (ii). To investigate the importance of protein aggregation in neuronal cell death after ischemia by employing conditions known to increase or decrease the amount of ischemic cell death, and by using animals overexpressing molecular chaperones known to protect unfolded protein from aggregation. (iii). To study the mechanisms of protein aggregation after ischemia using a variety of biochemical and molecular biological methods. There is virtually no drug directly protecting neurons against ischemia in the clinic. A short period of ischemia with reperfusion or incomplete ischemia causes a slow type of selective neuronal death in CA1 neurons after transient ischemia, in the penumbra area in ischemic stroke and in the ischemic region after thrombolytic treatment. This delayed secondary neuronal death has clinical significance because understanding the mechanisms will provide avenues to prevent the neuronal death. The protein aggregation after ischemia may contribute to ischemic neuronal death.
| 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 |
| Luo, Tianfei; Roman, Philip; Liu, Chunli et al. (2015) Upregulation of the GEF-H1 pathway after transient cerebral ischemia. Exp Neurol 263:306-13 |
| 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 |
| Kristian, Tibor; Hu, Bingren (2013) Guidelines for using mouse global cerebral ischemia models. Transl Stroke Res 4:343-50 |
| Park, Yujung; Luo, Tianfei; Zhang, Fan et al. (2013) Downregulation of Src-kinase and glutamate-receptor phosphorylation after traumatic brain injury. J Cereb Blood Flow Metab 33:1642-9 |
| 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 |
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