Therapeutic modulation of the complement system in neurodegenerative disease
The complement factors C3a and C5a are a potent inflammatory and immunomodulatory molecules. Inflammation is increasingly implicated in the progression of neurodegenerative disease. Our laboratory is investigating the effects of C3a and C5a in several models of neurodegenerative disease, including motor neuron disease (ALS), Parkinson's disease, and Huntington's disease, by using a specific C3a and C5a receptor therapeutics, and novel transgenic mice and tools developed by us and our collaborators. We are also working closely with neurologists at the Royal Brisbane & Women's Hospital, to help translate our knowledge into the clinic for the benefit of patients.
Novel neuroinflammation pathways driving ALS and Parkinson's disease
Our groups is also investigating other targets of the innate immune system, such as the NLRP3 inflammasome, as potential new targets to combat neuroinflammation in these diseases. We are collaborating with local and international groups to develop and test novel drugs which target these pathways in an effort to bring these treatments closer towards clinical trials.
Essential roles for the innate immune system in brain development
We have found that components of the innate immune system are expressed in human and mouse embryos, and are essential for aspects of neural development. Specific inhibition of the complement system impairs neurogenesis and brain formation, leading to dramatic neurodevelopmental defects. We are exploring the mechanisms by which this system helps to develop the brain, which will provide clues to what happens when things go wrong - and potential ways to combat this.
Active Grants as Principal Investigator (CIA):
Michael J. Fox Foundation: Target Validation grant (2015-2016). Pharmacological targeting of the NLRP3 inflammasome in pre-clinical models of Parkinson's disease using potent orally active inhibitors.
NHMRC Project Grant (2015-2019). Determining the contribution of peripheral immune complement signalling in the progression of motor neuron disease.
NHMRC Project grant (2015-2017). Complement activation as a therapeutic target and clinical biomarker for Parkinson's disease.
Coordination of 3rd year Biomedical courses, as well as teaching Pharmacology into several other Science and Medical courses.
PhD and Honours Projects
Students interested in undertaking Honours or research higher degrees are encouraged to contact A/Prof Woodruff. The following topics are broadly studied in his group:
- Arbore, Giuseppina, West, Erin E., Spolski, Rosanne, Robertson, Avril A. B., Klos, Andreas, Rheinheimer, Claudia, Dutow, Pavel, Woodruff, Trent M., Yu, Zu Xi, O'Neill, Luke A., Coll, Rebecca C., Sher, Alan, Leonard, Warren J., Koehl, Jorg, Monk, Pete, Cooper, Matthew A., Arno, Matthew, Afzali, Behdad, Lachmann, Helen J., Cope, Andrew P., Mayer-Barber, Katrin D. and Kemper, Claudia (2016) T helper 1 immunity requires complement-driven NLRP3 inflammasome activity in CD4+ T cells. Science, 352 6292: 1424+-U95. doi:10.1126/science.aad1210
- Croker, Daniel E., Monk, Peter N., Halai, Reena, Kaeslin, Geraldine, Schofield, Zoe, Wu, Mike C. L., Clark, Richard J., Blaskovich, Mark A. T., Morikis, Dimitrios, Floudas, Christodoulos A., Cooper, Matthew and Woodruff, Trent M. (2016) Discovery of functionally selective C5aR2 ligands: novel modulators of C5a signalling. Immunology and Cell Biology, 94 8: 787-795. doi:10.1038/icb.2016.43
- Nabizadeh, Jamileh A., Manthey, Helga D., Steyn, Frederik J., Chen, Weiyu, Widiapradja, Alexander, Akhir, Fazrena N. Md, Boyle, Glen M., Taylor, Stephen M., Woodruff, Trent M. and Rolfe, Barbara E. (2016) The complement C3a receptor contributes to melanoma tumorigenesis by inhibiting neutrophil and CD4+ T cell responses. Journal of Immunology, . doi:10.4049/jimmunol.1600210
- Brennan, Faith H., Lee, John D., Ruitenberg, Marc J. and Woodruff, Trent M. (2016) Therapeutic targeting of complement to modify disease course and improve outcomes in neurological conditions. Seminars in Immunology, 28 3: 292-308. doi:10.1016/j.smim.2016.03.015
- Mantovani, Susanna, Gordon, Richard, Li, Rui, Christie, Daniel C., Kumar, Vinod and Woodruff, Trent M. (2016) Motor deficits associated with Huntington's disease occur in the absence of striatal degeneration in BACHD transgenic mice. Human Molecular Genetics, 25 9: 1780-1791. doi:10.1093/hmg/ddw050
- Jeanes, Angela, Coulthard, Liam G., Mantovani, Susanna, Markham, Kathryn and Woodruff, Trent M. (2015) Co-ordinated expression of innate immune molecules during mouse neurulation. Molecular Immunology, 68 2: 253-260. doi:10.1016/j.molimm.2015.09.004
- Lee, Jia Y., Lee, John D., Phipps, Simon, Noakes, Peter G. and Woodruff, Trent M. (2015) Absence of toll-like receptor 4 (TLR4) extends survival in the hSOD1<sup>G93A</sup> mouse model of amyotrophic lateral sclerosis. Journal of Neuroinflammation, 12 1: . doi:10.1186/s12974-015-0310-z
- Coulthard, Liam G. and Woodruff, Trent M. (2015) Is the complement activation product C3a a proinflammatory molecule? Re-evaluating the evidence and the myth. Journal of Immunology, 194 8: 3542-3548. doi:10.4049/jimmunol.1403068
- Hawksworth, Owen A., Coulthard, Liam G., Taylor, Stephen M., Wolvetang, Ernst J. and Woodruff, Trent M. (2014) Brief report: Complement C5a promotes human embryonic stem cell pluripotency in the absence of FGF2. Stem Cells, 32 12: 3278-3284. doi:10.1002/stem.1801
- Mantovani, S., Gordon, R., Macmaw, J. K., Plfluger, C. M., Henderson, R. D., Noakes, P. G., McCombe, P. A. and Woodruff, T. M. (2014) Elevation of the terminal complement activation products C5a and C5b-9 in ALS patient blood. Journal of Neuroimmunology, 276 1-2: 213-218. doi:10.1016/j.jneuroim.2014.09.005
- Woodruff, Trent M., Lee, John D. and Noakes, Peter G. (2014) Role for terminal complement activation in amyotrophic lateral sclerosis disease progression. Proceeding of the National Academy of Sciences of the United States of America, 111 1: E3-E4. doi:10.1073/pnas.1321248111
- Lee, John D., Kamaruzaman, Nur A., Fung, Jenny N. T., Taylor, Stephen M., Turner, Bradley J., Atkin, Julie D., Woodruff, Trent M. and Noakes, Peter G. (2013) Dysregulation of the complement cascade in the hSOD1(G93A) transgenic mouse model of amyotrophic lateral sclerosis. Journal of Neuroinflammation, 10 . doi:10.1186/1742-2094-10-119
- Wu, Mike C. L., Brennan, Faith H., Lynch, Jason P. L., Mantovani, Susanna, Phipps, Simon, Wetsel, Rick A., Ruitenberg, Marc J., Taylor, Stephen M. and Woodruff, Trent M. (2013) The receptor for complement component C3a mediates protection from intestinal ischemia-reperfusion injuries by inhibiting neutrophil mobilization. Proceedings of the National Academy of Sciences of the United States of America, 110 23: 9439-9444. doi:10.1073/pnas.1218815110
- Li, Rui, Coulthard, Liam G., Wu, M. C. L., Taylor, Stephen M. and Woodruff, Trent M. (2013) C5L2: a controversial receptor of complement anaphylatoxin, C5a. FASEB Journal, 27 3: 855-864. doi:10.1096/fj.12-220509