Quick Project Snapshot
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 Ndfip1 in the brain 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. You will be using knockout mice without Ndfip1 and also mice engineered to over-express Ndfip1.
- 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) Divalent metal transporter 1 (DMT1) regulation by Ndfip1 prevents metal toxicity in human neurons. Proc. Natl. Acad. Sci. USA 106:15489-15494
- Schieber, C., Howitt, J., Putz, U., White, J.M., Parish, C.L., Donnelly, P.S. and Tan, S-S (2011) Cellular upregulation of Nedd4-family interacting protein 1 (Ndfip1) using low levels of bioactive cobalt complexes. J. Biol. Chem 286:8555-8564
- Howitt, J., Lackovic, J., Low, L-H., Naguib, A., Macintyre, A., Goh, C-P., Callaway, J.K., Hammond V., Thomas, T., Dixon, M., Putz, U. Silke, J., Bartlett, P., Yang, B., Kumar, S., Trotman, L.C., Tan, S-S. (2012). Ndfip1 regulates nuclear Pten import in vivo to promote neuronal survival following cerebral ischemia. J. Cell Biol. 196:29-36
- Lackovic, J., Howitt, J., Callaway, J.K., Silke, J., Bartlett, P., and Tan, S-S. (2012) Differential regulation of Nedd4 ubiquitin ligases and their adaptor protein Ndfip1 in a rat model of ischemic stroke. Exp. Neurol. 235:326-335
- Goh, C.P., Putz, U., Howitt, J., Low, L.H., Gunnersen, J., Bye, N., Morganti-Kossmann, C. and Tan, S-S. (2014) Nuclear trafficking of Pten after brain injury leads to neuron survival not death Exp. Neurol 252:37-46
Exosome Biology Laboratory
Brain cells are in constant communication with each other for transmitting electrical and chemical signals during mental activity. However, we believe that certain chemicals are also exchanged between brain cells for purposes that are not related to sensory and motor activity, for example for brain repair after injury. Brain communication is also important for protection of nerve cells against brain stress. We are currently engaged in discovering the nature of these communications and the circumstances behind their transmission.
We have been engaged in studying this natural method of communication using vesicles called exosomes. The exchanged material contains important messages (proteins, nucleic acids) that can have important consequences for cells that receive them. For example, in cancer, the spread of cancerous cells can be either hastened or retarded depending on the nature of these messages. Recently, we found out how to include certain additional messages that are normally not found in these exosomes. We are excited to study how these new messages can be used to repair brain cells after injury by boosting levels of repair proteins. In addition, we are enthusiastic about using these exosomes for transferring anti-cancer messages into brain tumours for reversing cancerous growth.
All Projects by this LabInvestigating interneuron migration and placement into cortical circuitsControl of protein transport in exosomes by Ndfip1How can Ndfip1 reduce brain damage following stroke?How does the brain protect itself during injury?Protein trafficking in neurodegenerative diseases.
Brain Development & Regeneration
Our group is interested in the self-defence mechanisms that operate in the brain when something goes wrong. This may take the form of degenerative disease (Parkinson's, Alzheimer's) or cancer (brain tumours) due to gene mutations and ageing. As a result, mutant or toxic proteins accumulate in brain cells, causing them to degenerate or proliferate. We have been working with one system of self-defence called protein ubiquitination which allows harmful proteins in brain cells to be removed and in the process, halt or reverse the disease process. We are particularly interested in finding how to accelerate beneficial ubiquitination in neurones using the Nedd4/Ndfip1 proteins. Our studies so far demonstrate that these proteins can halt cell death following injury and stroke, and slow down the division of brain cancer cells.