2005 First Cycle Individual Research Grant Recipients
$1,934,893

Carter, Bruce D., Ph.D., Vanderbilt University, Nashville, TN, United States
$150,000.00, 2-year Grant
The requirement for TRAF6 in p75 receptor mediated neurite inhibition
Research Category: Growth Inhibition

When the tip of a growing axon encounters certain proteins in myelin, the axon retracts like the cord of a window shade. In this project, Dr. Carter will focus on how these proteins exert this strong influence. Scientists already know that the receptors on the tip of an axon bind to the inhibitory proteins. This cleaving action launches a series of molecular signals that govern the behavior of the axon, but little is known about exactly how this mechanism halts the forward movement and causes the axon to pull back. Dr. Carter is interested in one of the receptors involved in this signaling, the p75 neurotrophin receptor. P75 plays a key role in cell death and survival, and scientists recently found it was linked to the Nogo Receptor, which interacts with powerful inhibitory proteins in myelin. Dr. Carter and his colleagues discovered that p75 teams up with a molecule called TRAF6 to function in cell survival and death. Because TRAF6 is so important in the signaling of the p75 receptor and because it seems that TRAF6 must be present for inhibitory proteins to stop axon growth, Dr. Carter hypothesizes that TRAF6 also is required for p75 to halt axon growth. He will test his theory in cell cultures, both with and without inhibitory proteins from myelin. He will assess axon growth from neurons taken from normal mice and from mice bred without TRAF6. If the cells from the genetically altered mice are not repelled by the proteins, then ¾ in theory ¾an agent that could deactivate or suppress TRAF6 following a spinal cord injury would enable axons to regenerate.

Cross, Kevin Jay, M.D., Weill Medical College of Cornell University, New York, NY, United States
$12,800.00, 1-year Grant
Hypoxia response element (HRE) promoter driven growth factor production for more rapid decubiti pressure sore closure.
Research Category: Concomitant Function

People with spinal cord injuries often suffer from wounds known as pressure sores, or decubitus ulcers, when they stay too long in the same position. The weight of their body pushes down on the skin that touches, say, a wheelchair or bed.  The compression keeps blood from flowing easily into the area and leads to oxygen deprivation, a condition called hypoxia. The oxygen-starved cells eventually die, and the skin breaks down, creating an avenue for infection that can spread quickly to the rest of the body. These ulcers can be complicated to treat and often require hospitalization. Care for a decubitus ulcer frequently involves difficult, time-consuming dressing changes, long courses of antibiotic, and surgical intervention. The most serious cases can lead to amputations or even death. The average cost of care approaches $70,000 per wound.

Dr. Cross, a plastic surgeon, has studied how the body tries to protect tissue that lacks oxygen by increasing the concentration of certain genes that control the production healing proteins. He hypothesizes that these genes also could be used in forms of gene therapy to treat decubitus ulcers. In this project, he will focus on a gene called hypoxia-inducible factor-1 (HIF-1) in an experiment that exploits the increased presence of HIF-1 around hypoxic cells. His approach involves another gene ¾  hypoxia-response element (HRE) ¾ that, when HIF-1 is present, increases the production of genes that are linked to it. Dr. Cross will genetically engineer HRE genes to ferry growth factor genes to the area of the wound. Growth factors are proteins that promote healing by, among other things, encouraging blood vessels to form and skin cells to grow near a wound. He expects HIF to bind to these piggyback genes and force the increased production of the desired growth factors. Other researchers have shown that this technique yields high levels of protein products, including growth factors. However, Dr. Cross hopes to be the first to prove that this system can be used to improve wound healing. Using a novel animal model he will see if his gene therapy is more effective than convention treatments in helping poorly healing decubitus ulcers to close.

Cotman, Carl W, Ph.D., University of California, Irvine, Irvine, CA, United States
$75,000.00, 1-year Grant
Mammalian CNS axonal mRNA
Research Category: Axon Guidance, Synapse Formation and Neurotransmission

In order for an axon to regrow after a spinal cord injury, the damaged stump must rebuild a structure at its tip called the growth cone. The surface of the growth cone is studded with receptor molecules.  These receptors pick up guidance cues in the extracellular environment and help to steer the elongating axon toward its final destination in the nervous system. Dogma held that axons could not make the proteins necessary to form the growth cone but instead used proteins that were manufactured in the cell body and then exported to the axon. However, recent evidence indicates that axons do synthesize the cytoskeletal proteins that maintain the shape of the axon and its tip and other key proteins as well. This local protein synthesis seems to be required for the growth and proper guidance of axons. Dr. Cotman, a prominent spinal cord researcher, is interested in how the genetic instructions, or mRNA (messenger RNA), direct the axon to make those crucial proteins. In this study, he hopes to discover which mRNAs are present in the axon and how local synthesis of proteins relates to the behavior the growth cone. Scientists have studied mRNAs extensively in peripheral axons, but they have not yet identified what types of mRNAs are at work in axons in the brain and spinal cord, in part because obtaining uncontaminated samples from axons in the central nervous system is quite difficult. Dr. Cotman’s laboratory has recently developed a novel technique to retrieve them. He then isolates the genetic material from axons and analyzes it to see which types of mRNAs are present and how the cast of mRNAs changes during regeneration. This data could make it possible one day to control the synthesis of proteins and boost the intrinsic capacity of the neuron to repair itself.

Galvez, Jose A, Ph.D., University of California, Irvine, Irvine, CA, United States
$120,000.00, 2-year Grant
Optimization of robotic control for automating gait training
Research Category: Rehabilitation

Increasing evidence shows that locomotor training can help people with spinal cord injuries regain some ability to walk over level ground. During the training, subjects are placed in a harness that supports their body weight over a treadmill.  Then assistants manually move the subjects’ feet in stepping motions. This labor-intensive process goes on daily for several months, making it inconvenient and expensive and, therefore, not widely available. Moreover, there is little data to show exactly how much and what type of manual assistance is best. Dr. Galvez would like to make locomotor therapy more accessible and affordable by replacing human trainers, which are in limited supply, with programmable robotic devices. These machines might even be better than human therapists because variables such as speed, the amount of assistance, and consistency of the training can be measured and controlled more accurately than they can with human trainers. However, Dr. Galvez maintains that early versions of robotic trainers are not “smart” enough. In other words, they cannot adapt to the needs of each person during a training session the way human trainers do; instead they usually just force the patient's legs through a walking motion.

Dr. Galvez and his colleagues have developed a machine that measures the forces and movements that human therapists apply to people’s feet during locomotor training. In this project, he will use this tool to identify the "smart," adaptive training techniques of experienced trainers. He then plans to implement these behaviors with a new computer-controlled, robotic device for locomotor training . Finally, he will analyze whether this robot does more to improve subjects’ muscle activity, effort, and stepping patterns than do standard robotic training techniques.

Giger, Roman J, Ph.D., University of Rochester Medical Center, Rochester, NY, United States
$150,000.00, 2-year Grant
Antagonism of myelin inhibition with a soluble synthetic Nogo receptor
Research Category: Axon Guidance, Synapse Formation and Neurotransmission

In this project, Dr. Giger will test a novel strategy to block the anti-growth substances in myelin. Underlying his approach are findings from other laboratories about an important protein called the Nogo receptor (NgR), a receptor for several of the growth-inhibiting proteins in myelin. Nogo receptors sit on the cell membrane of neurons, and when these receptors bind to a growth inhibitor, axons cannot regenerate. Other scientists have disrupted this mechanism by administering a soluble form of NgR that binds to growth inhibiting molecules before they can reach their intended receptors on the damaged neuron. This “pre-emptive” binding deactivates the growth inhibitors and has been shown to improve regeneration in animals with spinal cord injuries. Dr. Giger has identified another receptor, NgR2, that binds to a specific growth inhibitor called Nogo2. In laboratory studies, he and his team have used a soluble form of NgR2 to promote nerve growth in an environment that normally is hostile to regenerating axons. Using cutting-edge molecular biology, Dr. Giger and his team now created a synthetic molecule called NgRsyn that resembles both NgR and NgR2. When used in a soluble form, these imposter receptors harmlessly latch onto the growth inhibiting proteins, sopping them up so that they cannot bind to the genuine receptors and exert their growth-inhibiting influence. In this study, Dr. Giger will compare soluble NgR and soluble NgRsyn to see which promotes better recovery in rat models of spinal cord injuries. He expects that animals treated with soluble NgRsyn will fare better than those treated with soluble NgR1 will. If his hypothesis proves to be correct, this project could pave the way for human trials of this approach.

Hannila, Sari S, Ph.D., Hunter College, City University of New York, New York, NY, United States
$120,000.00, 2-year Grant
Enhancing axonal regeneration by administration of secretory leukocyte protease inhibitor
Research Category: Promotion of Axon Growth and Remyelination

This young researcher has her sights on a promising new approach that would protect surviving neurons after a spinal cord injury and suppress the powerful growth-inhibiting proteins in myelin. Dr. Hannila is exploring the treatment potential of an anti-bacterial protein called secretory leukocyte protease inhibitor (SLPI) that is abundant in saliva. Little is known about the role of SLPI in the nervous system, but other investigators have shown that it keeps brain neurons alive following a stroke. SLPI may also shield neurons following a spinal cord injury when immune cells flock to the lesion and release a damaging protein called elastase. Elastase kills neurons by disrupting their blood supply, but SLPI inactivates elastase and may curb the secondary cell loss. Dr. Hannila and her colleagues have also been studying whether SLPI helps to deactivate a key inhibitor of regeneration; a protein molecule called myelin-associated glycoprotein (MAG). These researchers proved that they could reduce the effects of MAG and improve axon regrowth by increasing the levels of a signaling molecule called cyclic AMP (cAMP). While analyzing just how cAMP keeps MAG in check, they discovered that cAMP greatly increases the production of SLPI. In preliminary studies, Dr. Hannila showed that neurons seeded onto layers of either MAG or myelin do not generate axons, but neurons treated with SLPI do. In this project, she will test whether SLPI alone can promote regeneration. She will administer SLPI to rats with spinal cord injuries and then assess the extent of regeneration and neuronal death. If her hypothesis is correct, SLPI may provide a two-for-one benefit in treating the injured spinal cord.

Henderson, Christopher E., Ph.D., Columbia University, New York, NY, United States
$150,000.00, 2-year Grant
Mechanism of action of JLK169, a cyclic polyamine that enhances axonal regeneration
Research Category: Promotion of Axon Growth and Remyelination

Jaffrey, Samie R, M.D., Ph.D., Weill Medical College of Cornell University, New York, NY, United States
$149,600.00, 2-year Grant
The role of RhoA mRNA translation in models of spinal cord injury
Research Category: Promotion of Axon Growth and Remyelination

Dr. Jaffrey is studying how some proteins in myelin stop regenerating axons in their tracks. These growth inhibitors appear to crank up the activity of a protein called RhoA, which regulates the structure of cells and causes regenerating axons to retract. Once RhoA is activated, the growth cone at the tip of an axon caves in, and the axon itself retracts. In this study, this young physician-scientist will follow up his discoveries that RhoA mRNA is enriched in axons and growth cones and determine whether translation of RhoA (production of RhoA protein) is required for GC collapse. These findings suggest that RhoA mRNA translation could be a key molecular event following a spinal cord injury. Dr. Jaffrey has designed several experiments to pinpoint just how prevalent this form of RhoA regulation is in injured axons. He also will try to find the mechanisms that regulate RhoA translation to see how the various growth-inhibiting proteins in myelin –such as Nogo, MAG ¾ affect RhoA. If he can decipher the signaling pathways that control RhoA, then it may be possible to develop a drug to block its action and improve axon regrowth and the recovery of function after a spinal cord injury.

Martin, John H., Ph.D., Research Foundation for Mental Hygiene, Inc., Columbia University, New York, NY, United States
$150,000.00, 2-year Grant
Electrical stimulation of the corticospinal tract after incomplete spinal cord injury
Research Category: Axon Guidance, Synapse Formation and Neurotransmission

In many spinal cord injuries, some nerve circuitry survives intact. Treatments that could strengthen those residual pathways could help people to recover some function. Working with animal models of incomplete spinal cord injuries, Dr. Martin has been evaluating the how electrically stimulation affects spinal nerves. He has previously shown that this stimulation promotes connections in the intact spinal cord of cats. In this study, he and his research team will test the approach on rats with experimental injuries to half their corticospinal tract. That tract is the main connection between the part of the brain that controls motor function and the spinal cord, and after this type of injury, the animals have difficulty using one side of their bodies. Researchers will implant electrodes into the intact half of the corticospinal tract to send electrical impulses to the spinal cord for two hours a day for three weeks. This stimulation will cause the synapses to fire at the ends of corticospinal nerves. To see how this technique works on new and older injuries, it will be tested on some animals immediately after injury and on others four weeks later. In both cases, Dr. Martin expects that the electrical stimulation will cause axon sprouting and new synapse formation in the spinal cord. These changes may enable the intact connections to exert better control over the impaired side of the body. To test this hypothesis, Dr. Martin and his team will evaluate changes in the animals’ movement and coordination, including how well they retrieve food pellets and climb ropes. Researchers also will measure the strength of modified connections. Finally, Dr. Martin will trace nerve fibers from the motor cortex to the spinal cord to examine the distribution and density of their connections. Each of the stimulated animals will be compared to non-stimulated controls. If this approach works, Dr. Martin predicts it could help people with both new and old spinal cord injuries, and the improvement would last after the therapy ended.

Paxinos, George, Ph.D., Prince of Wales Medical Research Institute, Sydney, NSW, Australia
$149,960.00, 2-year Grant
The Rat and Human Spinal Cord: Atlases and 3D Models
Research Category: New Tools for Spinal Cord Research

Just as a traveler uses a map to plan a journey, so spinal cord researchers need a detailed map of the spinal cord to understand the effects of injuries and to devise new treatments. Unfortunately, no precise, illustrated guides exist for the human spinal cord; in fact, no one has produced a comprehensive structural study of the spinal cord of any species. Dr. Paxinos will fill that void under this grant. He already has published world-renowned atlases of the humans brain as well as the brains of the monkey, rat, and mouse ¾ the most common experimental mammals. Now he will apply his expertise and sophisticated mapping techniques to the spinal cords of the rat, the mouse, and the human. In this project, Dr. Paxinos and his colleagues will create a comprehensive atlas as well as a three-dimensional, interactive model of the rodent spinal cord. Because the basic organization of the spinal cord is conserved across mammals, these tools also will improve scientists' understanding of the human spinal cord and enable them to visualize more clearly what happens during and after a spinal cord injury. Dr. Paxinos will highlight in the atlas relevant similarities between the human and rodent anatomy.  He also will analyze the neurochemistry of some samples of human spinal cord tissue to make initial comparisons between the chemical architecture of the rat and human cords. Having an accurate, complete map of the rat, mouse, and human spinal cord will accelerate the pace of spinal cord research, permitting neuroscientists to navigate seamlessly between the rat and human. Scientists can test hypotheses on the rat that were inspired by human considerations and then relate their findings back to humans.

Smith, Joseph Richard, Ph.D., University of Cambridge, Cambridge, , United Kingdom
$119,779.00, 2-year Grant
Generation of enriched motor neuron cultures from human embryonic stem cells
Research Category: Stem Cells

Dr. Smith will try to perfect a “recipe” for generating robust, dependable lines of motor neurons from human embryonic stem cells. Motor neurons are the nerve cells that activate muscles, and if large numbers of them could be derived from these very primitive cells, then the new cells could replace those damaged in a spinal cord injury. Other researchers have coaxed embryonic mouse stem cells from to evolve into motor neurons, and Dr. Smith will try to replicate that work with human cells in laboratory culture. He use a combination of genetic manipulation and two substances known to cause stem cells to proliferate and differentiate into neurons: a protein called sonic hedge hog and retinoic acid. He then will use advanced tools to identify, sort, and characterize the new motor neurons. If his approach is successful, it would give scientists a new, much-needed cellular model for studying how drugs, growth factors, and various other agents affect the survival and maturation of the newly generated motor neurons.  These human cells would have many advantages over mouse cells. For one, experiments that succeed on rodent models often prove disappointing in  human trials because of variations between the species. In addition, rodent and human development differ in significant ways, including how the central nervous system assembles. This project could provide neuroscientists with a new tool for research and, perhaps, a reliable way to create a pool of replacement cells that might one day rewire the injured spinal cord.

Vinay, Laurent, Ph.D., Centre National de la Recherche Scientifique (CNRS), Marseille, France
$149,040.00, 2-year Grant
Plasticity of inhibitory synaptic transmission during development and after adult spinal cord injury
Research Category: Concomitant Function

The orderly transmission of messages through the neural circuits of the brain and spinal cord depends on the synchronization of excitatory and inhibitory neurons. Excitatory neurons fire electrical impulses toward the next neuron in the chain, and inhibitory neurons do not. Without these quiet neurons, nerve circuits would be hyperactive or misfire. Dr. Vinay is interested how this crucial mechanism operates and how it is affected by spinal cord injuries. Normally, neurotransmitters, the chemicals that travel between neurons and enable them to communicate, control whether a neuron is excitatory or inhibitory. The transmitting neuron releases neurotransmitters, which then activate receptors on the surface of the receiving neuron. Whether that second neuron then sends the message along depends, in part, on the action of two neurotransmitters called GABA and glycine.  They can switch rapidly from inhibition to excitation and vice versa, depending on the concentration of chloride ion inside the receiving neuron. This concentration is regulated by a protein in the cell membrane called KCC2. When KCC2 is present and active, then GABA and glycine are inhibitory; when it is absent, these neurotransmitters are excitatory. KCC2 is scarce during early during development as well as in epilepsy and other pathological conditions, such as nerve injuries and chronic pain. In studies of rats, GABA and glycine switch to their inhibitory mode during the first postnatal week, when the connections between the brain and the spinal cord develop. Surprisingly little is known about how this mechanism works following a spinal cord injury.

In this study, Dr. Vinay will try to prove that nerve pathways descending from the brain reduce the action of KCC2 soon after birth and that spinal cord injury has a similar effect, causing GABA and glycine resume their excitatory function immediately after the trauma. He also will continue exploring the role of the brain in the maturation of inhibitory connections within the nerve circuits in the lower spinal cord known as central pattern generators.  These circuits generate the rhythmic movements needed for walking. If successful, this study could lead to treatments to protect tissue and restore function after SCI, and may help clinicians to amplify the effects of rehabilitation routines by improving the performance of important nerve circuits.

Whelan, Patrick John, Ph.D., University of Calgary, Calgary, AB, Canada
$132,880.00, 2-year Grant
The control of afferent transmission onto spinal locomotor pattern generators by monoamines.
Research Category: Concomitant Function

It comes as a surprise to many people that neurons within the spinal cord, rather than the brain, activate the muscles that produce our basic stepping pattern. Known as central pattern  generators, these spinal circuits communicate with nerve pathways in the brain stem that enable us to adjust to the challenges posed by, say, a moving escalator or a rutted path. Dr. Whelan and his colleagues are trying to understand how our brain normally communicates with the spinal circuits that generate walking. These researchers are particularly interested in how monoamines (dopamine, serotonin, noradrenaline) affect locomotor circuits. Monoamines are neurotransmitters that change the excitability of neurons within these pathways, influencing the speed and intensity of walking.  Animal models that receive monoamine therapy recover some walking ability, but why this approach succeeds is unknown. To investigate how monoamines control spinal circuits, Dr. Whelan uses a brainstem-spinal cord preparation with attached legs that is removed from the body of a developing mouse. These preparations can be kept “alive” in the laboratory for several days,, produce active walking, and contain the major centers in the brainstem that project to spinal cord locomotor regions. Dr. Whelan can precisely control the external environment of these preparations, so he can identify which monoamines act on the spinal circuits that generate walking.  In this project, he will try to identify which circuits are turned on by drugs that mimic the effects substances released when healthy people walk.  He will use brainstem-spinal cord preparations from mice that have been bred with a fluorescent protein in the spinal cord neurons that comprise their locomotor networks.  These neurons will then light up when activated. These observations could lead to drugs that would enhance rehabilitation therapy following a spinal cord injury.

Yang, Jaynie Frances, Ph.D., University of Alberta, Edmonton, Alberta, Canada
$149,886.00, 2-year Grant
Retraining of walking skills after spinal cord injury
Research Category: Rehabilitation

People with incomplete spinal cord injuries can regain some ability to walk after rigorous training during which they wear a weight-supporting harness and step on a treadmill. True walking, however, requires much more than simply ambulating on a smooth surface.  To accomplish what doctors call community walking, people must be able to negotiate an ever-changing landscape  ¾uneven surfaces, curbs, stairs, ramps ¾and carry objects while walking. Dr. Yang has developed a regimen that she predicts will enable people who have completed treadmill training to master the remaining challenges of community walking.  She wants to train people intensively in the skills they actually need in order to walk throughout the day in various locations. In this study, she will test the effectiveness of a varied training routine.  She will compare people who undergo her walking skills program with a control group that simply continues treadmill training. Both groups will train an hour a day, five times a week, for three months. Using a variety of measures, Dr. Yang will evaluate walking ability prior to training, at monthly intervals during training, at the end of training, and at three time points following training.  Subjects’ daily activity level also will be estimated at the same intervals by using an activity questionnaire.  At the end of training, the control group will have the chance to follow the new protocol for an additional three months.  Dr. Yang hypothesizes that her skill training will lead to better performance on function tests and greater participation in physical activity.  Her hope is that this training routine will enable more people with spinal cord injuries to live and work independently.  If their improved walking enables them to become more active, they may also reap important health benefits, including reduced spasticity; greater bone density; and better bowel, bladder and cardiovascular function. This approach to training could greatly improve the quality and length of their life.