Project 2:
How does the brain protect itself during injury?
Following brain injury, neurons die for days and even weeks after the event. Some neurons die as a consequence of the injury (e.g. trauma, stroke) but neurons in adjacent areas die from uncontrolled released of toxic substances and excessive firing activity. The brain tries to protect itself from this secondary cell death by increasing Ndfip1, a protein that is normally present at low levels but upregulated by stress. Neurons that increase Ndfip1 are protected from death; unfortunately this protective mechanism appears to be limited to a small number of participating neurons. The reason for this is unknown but it opens up a therapeutic opportunity. In this project, we seek to understand how endogenous Ndfip1 protects neurons from death, and to devise methods (e.g. drugs) of amplifying the Ndfip1 response to cover other neurons that normally succumb to death.
How can Ndfip1 reduce brain damage from stroke?
Stroke is the third most common cause of death. After the onset of cerebral ischemia, about 2 million neurons die per minute, mostly from brain tissue surrounding the hemorrhage. We have discovered that if neurons in these area increase their levels of Ndfip1, they are protected from death during the vulnerable period. In this project, we aim to test a number of drugs that are known to increase Ndfip1 in neurons. We will discover the molecular pathways that allow these drugs to upregulate Ndfip1, and therefore increase the number of surviving neurons following stroke.
Publications
1. Sang, Q., Kim, M., Kumar, S., Bye, N., Morganti-Kossman, M.C., Gunnersen, J., Fuller, S., Howitt, J., Hyde, L., Beissbarth, T., Scott, H.S., Silke,, J. and Tan, S-S (2006) Nedd4-WW domain-binding protein 5 (Ndfip1) is associated with neuronal survival following acute cortical brain injury. J. Neurosci. 26:7234-7244
2. Putz, U.,, Howitt, J., Lackovic, J., Foot, N., Kumar, S., Silke, J. and Tan, S-S (2008) Nedd4-family interacting protein 1 (Ndfip1) is required for the exosomal secretion of Nedd4-family proteins. J. Biol. Chem 283:32621-32627
3. Howitt, J., Putz, U., Lackovic, J., Doan, A., Dorstyn, L., Cheng, H., Yang, B., Chan-Ling, T., Silke, J., Kumar, S. and Tan, S-S (2009)
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