Arthur Brown, PhD


Arthur Brown, Principal Investigator

Why I Became a Scientist

For as long as I can remember I have been driven to find out how things work.  As a child I constantly asked my parents and teachers “how and why” questions.  How do batteries work?  How do motors work.  Why do compass needles point north?  And when it came to the workings of the human body there were no end to my questions.  Within the human body there is probably no greater mystery than the workings of the brain.  The brain is not only the master controller of all the other organs of the body but it also allows us to think, to emote and ponder our own existence.  It makes us what and who we are. I love being a neuroscientist – I get paid for investigating one of the greatest mysteries of life.

Research Summary

Recovery after spinal cord injury depends on the balance of pro- and anti-regenerative forces
Spinal cord injury is a catastrophic event that is a major health care issue, causing lifelong disability. In the USA and Canada, more than 12,000 spinal cord injuries occur annually, and ~275,000 people live with permanent, serious disabilities due to SCI.  Since spinal cord injury typically occurs in young adults it represents a lifelong burden to the patient and a socioeconomic challenge to our society. Currently, there are no effective treatments for spinal cord injury.   The body’s response to spinal cord injury includes processes that promote regeneration and processes that not only inhibit regeneration but actually increase damage.  The balance of these pro– and anti-regenerative forces determines the final clinical result.  We have three major areas of research focused on identifying and testing strategies to tip the balance of power away from damaging processes and towards productive healing.  Our research program includes anti-inflammatory strategies, cellular therapies and gene therapies  designed to harness the good part of the body’s response to spinal cord injury while limiting the bad parts of this natural response to injury.

Research Questions and Disease Implications

What role does inflammation play in spinal cord injury?

Mechanical injury to the spinal cord is followed by an inflammatory response that leads to a great deal of damage that gets worse with time.  However, inflammation also triggers processes such as wound healing that are of significant benefit.  Most of the damaging effects of inflammation are carried out by a subset of white blood cells called neutrophils.  In collaboration with the Weaver and Dekaban laboratories we are investigating the use of a monoclonal antibody that blocks these cells from entering the injured cord.  This experimental treatment has shown remarkable success in preclinical animal studies and is being further developed.

Can stem cell transplantation be used to improve outcomes from spinal cord injury?

The capacity for repair in the injured spinal cord is greatly impaired because the mature central nervous system, with rare exceptions, is unable to generate new neurons or to regenerate axonal connections.  Cell transplantation has therefore emerged as a promising treatment for spinal cord injury.  We have investigated the use of adult stem cells derived from bone marrow in a mouse model of spinal cord injury.  We have found that these stem cells promote repair of the spinal cord by promoting the repair and rescue of damaged tissue and by altering the expression of scar genes to promote regeneration.

Regeneration in the nervous system is hindered by the expression of  genes that block nerve growth.  What regulates the activation of these inhibitory genes?

The absence of axonal regeneration after spinal cord injury has been attributed to nerve-repelling molecules in the damaged myelin and scar. These inhibitory molecules in the scar are produced by reactive astrocytes responding to the injury.  However, astrocytes have also been shown to produce molecules that promote nerve growth. We have identified a master control gene that regulates the balance between the anti- and pro-regenerative genes activated after spinal cord injury.  We are currently devising strategies to block this master control gene so as to maximize the expression of pro-regenerative genes and minimize the expression of anti-regenerative genes after spinal cord injury.

Education

• Doctorate in Medical and Molecular Genetics, University of Toronto

Training

• Postdoctoral training in Neurodegeneration at the Institut du Cancer, Montreal
• Postdoctoral training in Neurodevelopment at the Salk Institute, San Diego, CA

Awards

• Doctorate in Medical and Molecular Genetics, University of Toronto
• Postdoctoral training in Neurodegeneration at the Institut du Cancer, Montreal
• Postdoctoral training in Neurodevelopment at the Salk Institute, San Diego, CA
• Heart and Stroke Foundation of Canada,  New Investigator’s Award,
• CIHR - SOX9 regulation of scar production after spinal cord injury
• CIHR - Leukocyte integrins as targets for neuroprotective strategies after spinal cord injury
• Morton Cure Paralysis Fund - Identifying SOX9 inhibitors to promote regeneration after spinal cord injury
• International Fund for Paralysis Research - Regeneration and recovery after spinal cord injury in a SOX9 knockout mouse

Publications

1. Weaver, L.C., Dekaban, G.A. and Brown, A. (2012).  Anti-CD11d monoclonal antibody treatment for rat spinal cord compression injury.  Experimental Neurology, 233(2): 612-4.

2. Shultz, S., Bao, F., Omaña, V., Chiu, C., Brown, A. and Cain P. (2012).  Repeated mild lateral fluid percussion brain injury in the rat causes cumulative long-term behavioural impairments, neuroinflamation and cortical loss in an animal model of repeated concussion.  J Neurotrauma, 29(2): 281-94.

3. Geremia, N.M., Bao, F., Rosenzweig, T.E., Hryciw, T., Weaver, L., Dekaban, G.A. and Brown A. (2011).  CD11d Antibody Treatment Improves Recovery in Spinal Cord-Injured Mice. J Neurotrauma, 29 (3): 539-550.

4. Thawer, S.G., Chadwick, K., Mawhinney, L., Brown, A., Dekaban, G.A.  Differential detection and distribution of macrophages populations in the injured spinal cord of the Lys-egfp-ki transgenic mouse.  Journal of Neuropathology and Experimental Neurology, 71 (3) 180-197.

5. Brennaman, LH., Zhang, X., Guan, H., Triplett, JW., Brown, A., Demyanenko, GP., Manis, PB., Landmesser, L.,  and Maness, PF.  (2011) Polysialylated and NCAM EphrinA/EphA to Regulate Synaptic Development of GABAergic Interneurons in Prefrontal Cortex.  Cerebral Cortex, [PMID: 22275477].

6. Bao, F., Omana, V., Brown, A., and Weaver, L. (2011).  The systemic inflammatory response after spinal cord injury in the rat is decreased by alpha4 beta1 integrin blockade. J Neurotrauma, [Epub ahead of print] [PMID:  22150233].

7. Xu, K., Geremia, N., Bao, F., Pniak, A., Rossoni, M. and Brown, A. (2011). Schwann cell co-cultured MSCs improve neurological outcomes in spinal cord injured mice.  Cell Transplantation, 20(7): 1065-86.

8. Bao, F., Brown, A., Dekaban, GA, Omana, V. and Weaver, L.C. (2011). CD11d integrin blockade reduces the systemic inflammatory response syndrome after spinal cord injury.  Journal of Experimental Neurology, 231(2): 272-83.

9. Bao, F., Bailey, C. S., Gurr, K. R., Bailey, S. I., Rosas-Arellano, M.P., Brown, A., Dekaban, G. and Weaver, L.C.  (2011). Human spinal cord injury causes specific changes in surface expression of leukocyte adhesion molecules.  Journal of Neurotrauma, 28(2): 269-80.

10. Bao, F., Markowski, M., Golshani, R., Pearse, D., Kasabov, L., Flemming, J.C., Brown, A. and Weaver, L.C. (2010). A selective phosphodiesterase-4 inhibitor reduces leukocyte infiltration, oxidative processes and tissue damage after spinal cord injury.  Journal of Neurotrauma, 28 (6): 1035 – 49.

11. Gonzalez-Lara, L., Xu, K., Hofstetrova, K., Pniak, A., Chen, Y., McFadden, C. D., Martinez-Santiesteban, F. M., Rutt, B.K.,  Brown, A. and Foster P.  (2010).  The Use of Cellular Magnetic Resonance Imaging To Track the Fate of Iron-Labeled Multipotent Stromal Cells after Direct Transplantation in a Mouse Model of Spinal Cord Injury.  Mol Imaging Biol., 13 (4): 702 – 11.

12. Gris, P. Tighe, A., Hemphill, A., Thawer, S., Dekaban, G. and Brown A. (2009). Gene expression profiling in anti-CD11d mAb-treated spinal cord-injured rats. J Neuroimmunol. 209 (1-2): 104-13.

13. Gonzalez-Lara, L., Xu, K., Hofstetrova, K., Pniak, A., Brown, A. and Foster P.  (2009).  In Vivo Magnetic Resonance Imaging of Spinal Cord Injury and Cell Therapy In Mice. J. Neurotrauma 26 (5): 753-62.

14. Marquardt, T., Gallarda1, B., Bonanomi1, D., Müller D., Brown, A., Alaynick, W., Andrews, S.E., Lemke, G., and Pfaff, S. (2008).  Functional delineation of sensory and motor pathways via heterotypic trans-axonal signaling. Science, 230 (5873): 233-236.

15. Gris, P. Tighe, A., Levin, D., Sharma, R. and Brown A. (2007).  Transcriptional regulation of scar gene expression in primary astrocytes.  Glia, 55(11): 1145-55.

16. Brown, A., Ricci, M-J. and Weaver L.C. (2007).  NGF mRNA is expressed in the dorsal root ganglia after spinal cord injury in the rat.  Experimental Neurology, 205(1): 283-6.

17. Stephen, L.E., Fawkes, A., Pniak, K., Pniak, A., Lemke, G. and Brown, A.  (2007). A critical role for the EphA3 receptor tyrosine kinase in heart development.  Developmental Biology, 302: 66-79.

Contact Information

abrown@robarts.ca