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John D. Houle, Ph.D.

John D. Houle, Ph.D.
Professor, Dept. Neurobiology and Anatomy, Drexel University College of Medicine
Email: jhoule@drexelmed.edu

Neurotransplantation Strategies to Promote Structural and Functional Recovery after Spinal Cord Injury

Research and Interest

Dr. Houle has a long standing interest in spinal cord injury and the potential to promote structural and functional repair in acute and chronic injury situations. It is important to understand that a spinal cord injury is an evolving condition where for weeks to months after injury there continues to be change/modulation of the cellular and molecular components affected directly or indirectly by the injury. These changes often are most prominent at the site of injury but it is critical that we also understand how cells/tissues remote to the injury are affected. An example would be the effect of spinal cord injury on neurons in the brain that normally transfer information through axon pathways that have been damaged. The response to injury by neurons in the brain may include cell atrophy, cell death,change in gene expression, retraction of the damaged axonal process or an attempt to re-grow the damaged axonal process.

Research in the laboratory is designed to examine multiple aspects of the neuronal and glial cell response to spinal cord injury with the intent of designing a combinatorial treatment strategy for regeneration leading to functional recovery. To accomplish this difficult task we use a variety of approaches, including: 1) neurotransplantation to provide a substratum that will support the regrowth of injured axons and which may provide a source of precursor cells to form new neurons and glial cells, replacing those lost after spinal cord injury; 2) treatment with neurotrophic and/or growth factors to provide essential molecules for cell survival and for initiating and maintaining axonal growth; 3) modulation of glial scar tissue and associated extracellular matrix to reduce the negative features of what has been characterized as a structural and chemical barrier to axonal growth; 4) exercise of injured limbs in the attempt to maintain joint fluidity and muscle strength and to re-train regions of the spinal cord that have been separated from descending input from the brain. There is strong evidence of activity dependent plasticity within the brain and spinal cord after exercise and we are especially interested in applying physical therapy and rehabilitation medicine techniques to determine if enhanced spinal cord plasticity will translate into greater behavioral recovery. As more information is gathered and placed into the puzzle, our understanding of the sequence of steps to be followed to promote recovery of function will become clearer.

Research techniques used in the laboratory range from gross anatomical examination to quantifying gene expression of single neurons. A typical experiment will include animal surgery, transplantation, physical therapy, a battery of behavioral analyses, preparation of tissue samples for light microscopy and immunocytochemical detection of specific cell types or tissue components, isolation of specific cells by laser micro dissection for extraction of RNA for analysis of gene expression by quantitative PCR, isolation of proteins for analysis of cell signaling by Western Blot or multiplex arrays.

Biography

John Houle did his Ph.D. at Purdue University and his postdoctoral fellowships at University of Saskatchewan and University of Florida. He later served on the faculty of the Department of Neurobiology and Developmental Sciences at the University of Arkansas for Medical Sciences. He is now a professor in the Department of Neurobiology and Anatomy at Drexel University College of Medicine.

Active Funding

R37 NS26380, (YEARS 16-22) John Houle, P.I. Dates of Project (Entire Period of Support) 4/04 - 3/11 NINDS - This is a Jacob Javits Merit Award given to Dr. Houle for outstanding neuroscience research "Axonal Growth in the Chronically Injured Spinal Cord" The objectives of this study are three fold: 1) determine if axonal growth beyond a peripheral nerve graft, back into the spinal cord, can be promoted by combining chondroitinase treatment with a neurotrophic factor supplement. Anatomical evidence of axonal regeneration will be correlated with behavioral tests of functional recovery; 2) determine if treatment with glial cell-line derived neurotrophic factor (GDNF) acutely after spinal cord injury promotes long term neuron survival and regeneration; 3) examine activated signaling pathways in chronically injured neurons after a second injury alone or with GDNF treatment.

R01 NS40008, (YEARS 1-5) John Houle, P.I., Dates of Project (Entire Period of Support) 9/00 - /8/05 NINDS Activity Dependent Plasticity after Spinal Cord Injury" The objectives of this study are to define structural, electrophysiological and biochemical changes that occur in spinal cord and muscle following a spinal cord injury. The effects of post injury intervention of transplantation of fetal spinal cord tissue and/or hind limb exercise on reorganization of spinal cord pathways and muscle properties will be examined. This project will be included with the 2005 renewal application for the Spinal Cord Injury Program Project.

Lab Members

Research Associate:
Dr. Megan Detloff

Graduate Students:
Rahul Sachdeva
Catherine Theisen
Kaitlin Ferrell

Research Assistants:
Theresa Connors
Scarlett Austin
Daniel Quiros-Molina
Danielle Kulich

Collaborators & Colleagues

Charlotte Peterson, Ph.D., University of Arkansas for Medical Sciences
Phillip Gardiner, Ph.D., University of Manitoba
Felix Eckenstein, Ph.D., University of Vermont

Selected Publications

1. Murphy RJL, Dupont-Versteegden EE, Peterson CA and Houle JD. 1991. Two experimental strategies to restore muscle mass in adult rats following spinal cord injury. Neurorehab Neural Repair 13:125-134.

2. Dupont-Versteegden EE, Murphy RJL, Houle JD, Gurley CM and Peterson CA. 2000. Mechanisms contributing to restoration of muscle size with exercise and fetal transplants after spinal cord injury. Am. J. Physiol. 279: C1677-C1684.

3. Peterson CA, Murphy RJL, Dupont-Versteegden EE and Houle JD. 2001. Cycling exercise and fetal spinal cord transplantation act synergistically on atrophied muscle following chronic spinal cord injury in rats. Neurorehab and Neural Repair 14: 85-91.

4. Dolbeare D and Houle JD. 2003 Glial cell line-derived neurotrophic factor (GDNF) promotes neuroprotection and neurorepair after spinal cord injury. J. Neurotrauma 20: 1251-1261.

5. Beaumont E, Houle JD, Peterson CF and Gardiner PF. 2004. Fetal spinal cord transplant and passive exercise help to restore motoneuronal properties after spinal cord transection in rats. Muscle & Nerve 29:234-242.

6. Houle JD, Tom VJ, Mayes D, Wagoner G, Phillips N, Silver J. 2006. Combining an autologous peripheral nervous system "bridge" and matrix modification by chondroitinase allows robust, functional regeneration beyond a hemisection lesion of the adult rat spinal cord. J Neurosci. 26(28):7405-15.

7. Sandrow HR, Shumsky JS, Amin A, Houle JD. 2008. Aspiration of a cervical spinal contusion injury in preparation for delayed peripheral nerve grafting does not impair forelimb behavior or axon regeneration. Exp Neurol. 210(2):489-500.

8.Tom VJ, Houlé JD. 2008. Intraspinal microinjection of chondroitinase ABC following injury promotes axonal regeneration out of a peripheral nerve graft bridge. Exp Neurol. 211(1):315-9

9. Xi D, Keeler B, Zhang W, Houle JD, Gao WJ. 2009. NMDA receptor subunit expression in GABAergic interneurons in the prefrontal cortex: application of laser microdissection technique. J Neurosci Methods.176(2):172-81.

10. Sandrow-Feinberg HR, Izzi J, Shumsky JS, Zhukareva V, Houle JD. 2009. Forced exercise as a rehabilitation strategy after unilateral cervical spinal cord contusion injury.J Neurotrauma. 26(5):721-31.

11. Tom VJ, Kadakia R, Santi L, Houlé JD. 2009. Administration of chondroitinase ABC rostral or caudal to a spinal cord injury site promotes anatomical but not functional plasticity.J Neurotrauma. ;26(12):2323-33.

12. Houle JD, Amin A, Cote MP, Lemay M, Miller K, Sandrow H, Santi L, Shumsky J, Tom V. 2009. Combining peripheral nerve grafting and matrix modulation to repair the injured rat spinal cord. J Vis Exp. (33). pii: 1324. doi: 10.3791/1324.

13. Tom VJ, Sandrow-Feinberg HR, Miller K, Santi L, Connors T, Lemay MA, Houlé JD. 2009. Combining peripheral nerve grafts and chondroitinase promotes functional axonal regeneration in the chronically injured spinal cord. J Neurosci. 29(47):14881-90.

14. Sandrow-Feinberg HR, Zhukareva V, Santi L, Miller K, Shumsky JS, Baker DP, Houle JD. 2010. PEGylated interferon-beta modulates the acute inflammatory response and recovery when combined with forced exercise following cervical spinal contusion injury. Exp Neurol. 223(2):439-51.

15. Zhukareva V, Obrocka M, Houle JD, Fischer I, Neuhuber B. 2010. Secretion profile of human bone marrow stromal cells: donor variability and response to inflammatory stimuli. Cytokine. 50(3):317-21.

16. Lanvin, K., Keeler, B., Lemay, M., Houle, J.D. 2010 Proprioceptive neuropathy affects normalization of the H-reflex by exercise after spinal cord injury. Exp. Neurology 221:198-205. PMID: 19913536.

17. Côté, M.-P., A. Hanna, M.A. Lemay, K. Ollivier-Lanvin, L. Santi, K. Miller, R. Monaghan, J.D. Houle. 2010 Peripheral nerve grafts after cervical spinal cord injury in adult cats. Exp. Neurol. 225: 173-182.

18. Liu, G. B.E. Keeler, V. Zhukareva, J.D. Houle 2010 Cycling exercise affects the expression of apoptosis-associated miRNAs after spinal cord injury in rats. Exp. Neurol. 226:200-206.

19. Singh, A., M. Murray, J.D. Houle. 2011 A training paradigm to enhance motor recovery in contused rats: Effects of staircase training. Neurorehab. Neural Repair 25: 24-34.

20. Côté, M.-P., G.A. Azzam, M.A. Lemay, V. Zhukareva, J.D. Houlé. 2011 Activity-dependent increase in neurotrophic factors is associated with an enhanced modulation of spinal reflexes after SCI. J. Neurotrauma 28:1-11.

21. Côté, M.-P., A. Amin, V.J. Tom, J.D. Houlé 2011 Peripheral nerve grafts support regeneration after spinal cord injury. Neurotherapeutics 8:294-303.

22. Singh, A., S. Balasubramanian, M. Murray, M. Lemay, J. D. Houle. 2011 Role of Spared Pathways in Locomotor Recovery after Body Weight Supported Treadmill Training in Contused Rats, J Neurotrauma 28:1-12.

23. Murray, M., L. Santi, R. Monaghan, J.D. Houle, G.A. Barr. 2011 Microarray analysis of axotomized and of regenerating lateral vestibular neurons in rats. J. Comp. Neurol. 519: 3433-3455.

24. Liu, G., M.R. Detloff, K.N. Miller, L. Santi, J.D. Houle. 2011 Exercise modulates microRNAs that regulate the PTEN/mTOR pathway in rats after spinal cord injury. Exp Neuro. 233: 447-456.

25. Keeler, B.E., G. Liu, R.N. Siegfried, V. Zhukareva, M. Murray, J.D. Houle 2012 Acute and prolonged hindlimb exercise elicits different gene expression in motoneurons than sensory neurons after spinal cord injury. Brain Research 1438: 8-21.

26. Côté, M.-P., M.R. Detloff, R.E. Wade, M.A. Lemay, J.D. Houle 2012 Plasticity in ascending long propriospinal and descending supraspinal pathways in chronic cervical spinal cord injured rats. Frontiers in Physiology 3: Article 330, pp1-15.

27. Detloff, M.R., R.E. Wade Jr. and J.D. Houle 2013 Chronic at- and below-level pain following unilateral cervical spinal cord contusion in rats. J. Neurotrauma 30:884-890.

28. Tom, V.T., Sandrow-Feinberg, H.R., Miller, K., Domitrovich, C., Bouyer, J., Zhukareva, V., Klaw, M.C., Lemay, M.A., Houle, J.D. 2013 Exogenous BDNF enhances the integration of chronically injured axons that regenerate through a peripheral nerve grafted into a chondroitinase-treated spinal cord injury site. Exp. Neurol. 239: 91-100.

29. Houle, J.D. and Côté, M.P. 2013 Axon regeneration and exercise-dependent plasticity after spinal cord injury. Ann NYAS 1279: 154-163.

30. Detloff MR, Smith EJ, Quiros Molina D, Ganzer PD, Houlé JD. 2014 Acute exercise prevents the development of neuropathic pain and the sprouting of non-peptidergic (GDNF- and artemin-responsive) c-fibers after spinal cord injury. Exp Neurol. 255:38-48.

31. Ollivier-Lanvin K, Fischer I, Tom V, Houlé JD, Lemay MA. 2014 Either Brain-Derived Neurotrophic Factor or Neurotrophin-3 Only Neurotrophin-Producing Grafts Promote Locomotor Recovery in Untrained Spinalized Cats. Neurorehab Neural Repair.

32. Côté MP, Gandhi S, Zambrotta M, Houlé JD. 2014 Exercise modulates chloride homeostasis after spinal cord injury. J Neurosci. 2014 34(27):8976-87.