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 Personnel

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. Ye, J.H. and J.D. Houle 1997 Treatment of the chronically injured spinal cord with neurotrophic factors can promote axonal regeneration from supraspinal neurons. Exp. Neurol. 143:70-81.

2. Dupont-Versteegden, E.E., R.J.L. Murphy, J.D. Houle, C.M. Gurley and C.A. Peterson 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, C.A., R.J.L. Murphy, E.E. Dupont-Versteegden and J.D. Houle 2000 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. Storer, P.D., D. Dolbeare and J.D. Houle 2003 Treatment of the chronically injured spinal cord with neurotrophic factors stimulates BII-tubulin and GAP-43 expression in rubrospinal tract neurons. J. Neurosci. Res. 74: 502-511.

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

6. Dupont-Versteegden, E.E., J.D. Houle, R.A. Dennis, J.-M. Zhang, M. Knox, G. Wagoner and C.A. Peterson 2004 Exercise-induced gene expression in soleus muscles is dependent on time after spinal cord injury in rats. Muscle & Nerve 29: 73-81.

7. Houle, J.D. and A. Tessler. 2003 Repair of chronic spinal cord injury. Exp. Neurol. 182: 247-260.