NEURAL REPAIR AND REHABILITATION

PROGRAM SUMMARY


The notion that new brain cells can form and injured nerve fibers can regenerate has become accepted only over the past 15 years. Many opportunities appear to exist to repair the brain, spinal cord or the nerves that travel to the limbs to reverse paralysis.

The fundamental biological controllers for the extension of damaged nerves back to their targets on neurons or muscle (genes, proteins, inhibitors and attractors of growth at the tips of axons) can be partially manipulated in experiments, but no proof of this concept in patients yet exists.

The APNRR collaborations aim to identify the most promising drives for axon regeneration, for the use of stem cells and their differentiated offspring derived from different sources, and for sheathing axon fibers with myelin so they can conduct their electrical pulses. In addition, these scientists aim to manipulate basic mechanisms of learning and memory at synapses to maximize compensation by whatever spared neural networks may remain and to optimize the functional incorporation of restored pathways.

The group shares its procedures and biological measures across a variety of models of neurological disease, including spinal cord injury, stroke, brain trauma, ALS, multiple sclerosis, peripheral neuropathies, and optic nerve injury. Common denominators for driving mechanisms of recovery may be identified across these diseases.

The APNRR group aims for a proof of concept that biological therapies, medications that act on key targets, and engineering strategies will be able to augment rehabilitation therapies in disabled people.

Director:

S. THOMAS CARMICHAEL

Dr. S. Thomas Carmichael, MD, PhD is an Associate Professor of Neurology at the Geffen School of Medicine at UCLA. He has an active laboratory and clinical interests in stroke, neurorehabilitation, and mechanisms of brain repair after injury. He received his M.D. and Ph.D. degrees from Washington University School of Medicine and completed a Neurology residency there as well. Dr. Carmichael was a Howard Hughes Medical Institute postdoctoral fellow at UCLA from 1998-2001, studying mechanisms of axonal sprouting with a clinical emphasis on neurorehabilitation and stroke. Dr. Carmichael is a charter member of NIH Study Section BINP, on the editorial boards of Neurorehabilitation and Neural Repair and the Journal of Neurodegeneration and Regeneration and is director of didactics in the training program for UCLA neurology residents. His clinical work includes serving as an attending physician on the UCLA inpatient neurologic rehabilitation unit and on the acute stroke service.

Dr. Carmichael's laboratory studies the molecular and cellular mechanisms of neural repair after stroke and other forms of focal brain injury. Recent research has led to the surprising discoveries that the adult brain is capable of forming new connections after stroke (termed axonal sprouting) and is capable of recruiting adult brain stem cells to areas of injury (termed post-stroke neurogenesis). If properly harnessed, these two processes hold the promise of regenerating and reconnecting brain cells near areas of injury. Studies in the Carmichael lab are determining the molecules that control axonal sprouting and neurogenesis, so that new therapies can be developed that promote brain repair after stroke. The fact that the adult brain is capable of axonal sprouting and neurogenesis after stroke indicates that stroke induces a region of great structural change, or plasticity, near areas of damage. In a third avenue of investigation, the Carmichael laboratory is identifying these areas of brain plasticity after stroke as candidate regions for neural stem cell transplantation to promote recovery and restoration of function after stroke. This research has led to the finding that the novel post-injury environment near the lesion in the brain supports repair and regeneration after stroke. In this region, new blood vessels are formed and secrete growth factors that stimulate neural stem cells to become neurons. Also within this regenerative brain environment after stroke, molecules are expressed that promote the formation of new connections or axonal sprouting. Our present work focuses on developing drugs that will influence this environment for repair after stroke and optimize the substrate for retraining-induced gains from rehabilitation. Dr. Carmichael has been a key collaborating scientist in the APNRR since it began and assumed the role of Program Director in 2008.

© 2009 DR. MIRIAM AND SHELDON G. ADELSON MEDICAL RESEARCH FOUNDATION
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