2006 Individual Research Grant Recipients
$62,500.00, 1-year Grant This young researcher theorizes that fibrin, a protein that promotes blood clotting, may play a key role in inhibiting the regeneration of axons following a spinal cord injury. Concentrations of fibrin quickly rise around any kind of wound, including those in the central nervous system. Dr. Akassoglou hopes to demonstrate that by preventing the formation of fibrin, or by blocking its action, axons would regrow in the injured spinal cord. Using mouse models, she will explore the role of fibrin in two ways. First, she will see whether mice bred without the ability to produce fibrin recover more function than normal mice following spinal cord injuries. Second, she will administer two therapeutic drugs that prevent the formation of blood clots, ReoPro and Ancrod, to see whether they improve axon regrowth and recovery of function. The FDA already has approved ReoPro as a treatment in heart patients, and Ancrod is approved in Europe to treat strokes and is under consideration for approval in The United States. If this novel approach to promoting spinal cord repair proves successful, it could lead to human clinical trials. Borisoff, Jaimie, Ph.D., Neil Squire Brain Interface Lab Burnaby, BC, Canada Concomitant Function Spinal cord injuries often impair people’s ability to experience sexual sensations, even though some who are living with spinal cord injuries are still capable of arousal and, in the case of men, ejaculation. This researcher believes that a new approach called sensory substitution technology might enhance the sex lives of men with spinal cord injuries. This technology involves substituting perceptions from one sense for those from another. Reading Braille with the fingers is a low-tech version of this phenomenon. In a newer, more sophisticated application, signals from a video camera are transmitted to a grid of electrodes on the back or elsewhere, that in turn send painless impulses to the skin. Eventually, the brain learns to interpret the patterns of those sensations as sight. Another system under development uses signals on the tongue to help people with severe balance problems interpret their position and maintain their equilibrium. Dr. Borisoff’s experiment will also use the tongue as the substitute sensory receiver. The tongue is ideal for this purpose because it is rich in nerve endings that are closer to the surface and more sensitive than nerve endings in many other parts of the body. In addition, saliva is an excellent conductor of electricity. In this study, Dr. Forisoff will record the muscle activity from the pelvic floor that occurs during the build-up towards ejaculation in men with and without a spinal cord injury. He then will try to map this activity onto an electrical stimulation tongue input device called The BrainPort™, which is now awaiting FDA approval as a balance correction tool. The mouthpiece for BrainPort contains an array of low-voltage electrodes that will stimulate the tongue. Dr. Borisoff hypothesizes that, after several test sessions, subjects will associate the tongue stimulation with sexual pleasure. Dr. Borisoff plans to develop a prototype of a sexual sensory substitution device and to test it on healthy men and those with spinal cord injuries. Positive results would represent the first time scientists will have restored sensory loss in spinal cord injured men. Positive results could have a major impact on the quality of life for the spinal cord injured, many of whom rank the restoration of sexual health above or equal to the recovery of walking. Chan, Jonah R., Ph.D. University of Southern California, Zilkha Neurogenetic Institute, Los Angeles, CA $125,000.00, 2-year Grant Myelin is a fatty insulation produced by nerve cells called oligodendrocytes. It surrounds axons and is essential for the transmission of electrical signals through our nervous system. Although some axons --most notably nociceptive, or pain, neurons that enable us to perceive discomfort--are always unmyelinated and work fine this way, demyelinated axons do not. Injuries and diseases that destroy myelin disrupt vital signaling, harm the axon, and rob people of function. This young investigator is interested in the basic molecular mechanisms along axons themselves that appear to control the myelination process during development, causing oligodendrocytes to coat some axons in myelin and ignore others. Dr. Chan hopes to identify the specific molecules and signaling pathways that establish the proper environment for myelination. This study will build on his recent discovery that nerve growth factor (NGF), a naturally occurring substance that promotes the early survival and maturation of particular sets of neurons, also triggers the signals that control whether those axons will be myelinated. This finding provides a unique and valuable experimental foothold from which to characterize the key promoters and inhibitors of myelination. By understanding these processes, scientists may one day learn whether to mimic them or increase their activity in order to treat demyelinating injuries, like spinal cord injuries and strokes, and diseases that attack myelin, like multiple sclerosis. Cotman, Carl W., Ph.D., University of California, Irvine, Irvine, CA $62,500.00, 1-year Grant 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 that pick up guidance cues around them and 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 as well as other key proteins. 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 messenger RNA (mRNA ) that carries the cell’s genetic instructions, directs the axon to make those crucial proteins. This grant finances the second year of his study, which is designed to identify the mRNAs in the axon and to describe 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 mRNAs are present and how the cast of mRNAs changes during regeneration. In the first year of the study, Dr. Cotman and his colleagues confirmed that they could identify mRNAs present in growing and maturing axons. They were surprised to discover that axons in the central nervous system contain many more mRNAs than predicted. Initial data also has yielded new insights into key proteins that may be under local control. Some of these proteins may regulate axonal regeneration. Now these researchers will examine the mRNAs present in axons following injury and 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. El Manira, Abdeljabbar, Ph.D., Karolinska Institutet, Stockholm, Sweden $125,000.00, 2-year Grant The lower spinal cord contains specialized nerve circuits called the central pattern generator (CPG) that fire the rhythmic impulses needed for walking. A spinal cord injury cuts off communication between the brain and these circuits, causing paralysis. Most studies attempting to restore locomotor function after spinal cord injury have focused on substituting the missing transmitter descending from the brain or repairing the injured axons. In the last decade, however, scientists have turned their attention to the intrinsic ability of the spinal cord to reshape itself after an injury and of the central pattern generator to work without input from the brain. Dr. El Manira wants to study these mechanisms more closely. Using adult zebra fish, he will conduct a two-part study to examine the organization of the spinal locomotor circuitry and how it changes following injury. A zebrafish is an ideal model because the neural circuitry of its spinal cord is visible and easy to manipulate. In the first part of the study, Dr. El Manira will use electrophysiological, anatomical, molecular, and pharmacological techniques to examine the zebra fish spinal cord before and after an injury. He and his team will also test what happens when they silence specific genes thought to play an important role in the organization of the spinal circuitry before and after an injury as well as in generation of the locomotor activity. In the second part of this study, Dr. El Manira will study the unusual capacity of adult zebrafish to recover the ability to swim after spinal cord injury. He will try to describe precisely how the zebrafish spinal cord adapts to an injury and restores the lost function. The results from this study could lead to novel therapies that tap into the power of the spinal cord to reshape itself following trauma. Gross, Ted S., Ph.D., University of Washington, Seattle, WA
Osteoporosis is a serious complication of spinal cord injuries that increases the risk of fractures and affects the metabolism of calcium. Dr. Gross has recently developed a novel mouse model of bone loss that will enable him to study this destructive process and to test interventions to prevent or reverse it. He and his colleagues use Botox® to paralyze the quadriceps and calf muscles, which induces rapid and profound muscle and bone degradation. Bone loss in the mouse model was almost entirely driven by rapidly induced bone resorption. This cellular process is identical to the underlying cause of bone loss following spinal cord injury. In preliminary experiments, Dr. Gross’s team showed that brief, daily external muscle stimulation of the quadriceps muscles significantly mitigated bone loss in the mouse model. Dr. Gross hypothesizes that a window of opportunity exists when external muscle stimulation must be initiated in order to mitigate bone loss due to muscle paralysis. He will test his hypothesis in this two-part study. First, he will determine just how muscle stimulation mitigates bone loss. Second, he will try to pinpoint when muscle stimulation must begin to significantly diminish the resorption of bone. He suspects that delays of more than a few days will substantially compromise the success of this treatment. Results from his study may lead new rehabilitation protocols to prevent a major complication of spinal cord injury. Harris-Warrick, Ronald Morgan, Ph.D., Cornell University, Ithaca, NY $125,000.00, 2-year Grant The central pattern generator is the neural network in the lower spinal cord that orchestrates the muscle movements needed for walking. Signals from the brain turn this network on or off and direct it activity. After spinal cord injury, these control signals are lost, the spinal network stops working, and paralysis results. Dr. Harris-Warrick studies how the signals from the brain affect what happens in the nerve circuits involved in walking. He believes that the circuitry that runs down from the brain includes not only rapid pathways to turn on the neural network but also slower modulatory pathways that prime the neural network for firing. He likens these slow pathways to a car key that starts the engine and leaves it idling; the rapid pathways function like a driver who steps on the accelerator to get the car moving. Restoring only the rapid pathways following a spinal cord injury would be like depressing the gas pedal with the engine off. In the project, Dr. Harris-Warrick will study how these slow modulatory signals enable the locomotor network to reach and maintain its idling state. He hypothesizes that the neurotransmitter serotonin alters two sets of spinal neurons, preparing them to activate rhythmic locomotor behavior once the rapid pathways fire. In this project, Dr. Harris-Warrick and his team will look at how serotonin changes the firing properties of the spinal neurons. The results of this study could provide the rational for testing serotonin and other modulatory drugs as a first-line treatment after spinal cord injury. Ideally, these drugs would maintain the locomotor network neurons in an‘idling’ state. Then, if doctors could restore the fast activating pathways, the network would be primed to operate and restore walking. Kaas, Jon, Ph.D., Vanderbilt University, Nashville, TN $125,000.00, 2-year Grant Dr. Kaas plans to test in monkeys two procedures known to promote the growth of new axons and to aid in the recovery of function after spinal cord injury. He will focus on the nerves that transmit input from the forelimbs in the dorsal columns of the spinal cord, the area processes sensory information. If only a few of these nerves survive an injury, they can become more effective and promote recovery by sprouting more axons. These new axons then hook up with neurons in the cuneate nucleus of the brainstem that transmits information to the higher brain. Dr. Kaas and his team will attempt to enhance this new growth --or collateral sprouting-- in surviving nerve cells by counteracting two naturally occurring substances that interfere with growth after an injury. At the time of injury in one group of animals, the researchers will administer an enzyme called chondroitinase ABC to digest anti-growth substances in the extracellular matrix surrounding neurons in the cuneate nucleus. A second group will receive a continuous infusion for four weeks of an anti-body that neutralizes the growth-inhibitory molecule Nogo-A. Dr. Kaas then will assess the monkeys’ recovery by taking electrical readings and by testing how well the treated monkeys can pick up food pellets compared to untreated controls. Two months after the injury, he will look for new axon growth in the cuneate nucleus and measure the extent of nerve reactivation with readings from microelectrodes. If, as Dr. Kaas expects, both treated groups fare better than the control group, then this study could be an important step in developing treatments for human spinal cord injuries. Matheny, Sharon A., Ph.D., University of Texas Southwestern Medical Center, Dallas, TX $119,988.00, 2-year Grant In the healthy spinal cord, a sheath of myelin surrounds and insulates axons, enabling them to function normally. After an injury, however, myelin becomes more foe than friend, creating an extremely inhospitable environment for regenerating lost nerves. Scientists have begun to identify and study some components of myelin that stymie regrowth, including the protein ephrin-B3 (EB3). Dr. Matheny is interested in the molecular mechanisms at play between EB3 and its receptor EphA4 on corticospinal neurons, which run from the cerebral cortex to the spinal cord. Knowing just how inhibitory signals move from cell to cell is a key step in designing drugs to encourage recovery after an injury. This young scientist will try to unravel the signaling pathways that enable EB3 to activate EphA4. She will also explore how EphA4 activates some of the same molecules as another receptor, p75/NgR, the receptor for three other powerful myelin proteins: Nogo, MAG, and Omgp. If she discovers that these receptor systems influence each other within the axon, then perhaps a treatment could be developed that would simultaneously block both. Pfaff, Samuel L., Ph.D., The Salk Institute for Biological Studies, La Jolla, CA $125,000.00, 2-year Grant The Pfaff Laboratory is well-known for its research on the genes involved in the development of the spinal cord. In this study, Dr. Pfaff and his colleagues will focus on the neurons within the lower spinal cord that comprise the central pattern generator (CPG ). This complex network of cells can generate locomotor activity – even if connections between the brain and the spinal cord have been lost. Although the discovery of the CPG occurred nearly a century ago, the actual identity of the cells that participate in these spinal circuits remains fragmentary. This study focuses on how motoneurons, the nerve cells that activate muscles, and interneurons, the cells that link one neuron to another, organize themselves into the CPG and establish locomotor activity in the spinal cord. Researchers will use several types of genetically engineered mouse lines to try to pinpoint the master genes that control the position and role of neurons in the CPG. Dr. Pfaff will use electrophysiological recordings and sophisticated cell-labeling techniques to examine spinal circuitry in the mouse models. These experiments could help scientists understand how motoneurons form new connections following a spinal cord injury. Stein, Richard Bernard, Ph.D., University of Alberta Edmonton, AB, Canada $125,000.00, 2-year Grant An expert in physiology, neuroscience, and biomechanics, Dr. Stein has developed several noninvasive devices to help people with spinal cord injuries to walk. These aides use mild electrical current to stimulate contractions in muscles that have been paralyzed, a technology called functional electrical stimulation (FES). For example, WalkAide, a band worn beneath the knee, restores nerve-to-muscle signals in the leg and foot, effectively lifting the foot at the appropriate time. WalkAide reduces a condition known as foot drop, in which someone with an incomplete spinal cord injury or other neurological problem cannot properly flex an ankle, causing the foot on that side to drag during walking. Dr. Stein and his associates also have combine FES with braces that enable people with complete spinal cord injury to walk. The bracing provides stability and limits muscle fatigue, while the stimulation provides propulsion. Although both devices represent advances over previous systems, users still have problems such as fatigue of some muscle groups and unreliable reflexes. Moreover, people with injured spinal cords often lack the sensory feedback needed to adjust their stepping to changes in external conditions, like uneven terrain, or internal changes, like fatigue. Dr. Stein has been perfecting implantable arrays of microelectrodes that record input from sensory neurons. These recordings can provide the feedback needed to change from one phase to the next of the walking cycle. In this study, Dr. Stein will team up with Dr. Vivian Mushahwar, an expert in intraspinal microstimulation(ISMS). She implants microelectrodes, as fine as hair, into the spinal cord to generate controlled muscle contractions in the legs. Activating muscles in the appropriate sequences, these microwires produces a walking-like movement. In this study, Dr. Stein and Mushahwar will test in cat models a prototype of a walking aide that, for the first time, combines ISMS with sensory feedback. They expect this dual approach to be much more adaptable to external obstacles, more efficient in terms of the energy required to walk, and better at controlling balance and speed. If these predictions are confirmed in this project, then humans trials could soon follow because all the materials in the prototype are approved for use in humans. Twiss, Jeffery Lewis, M.D., Ph.D., Alfred I duPont Hospital for Children, Wilmington, DE $120,725.00, 2-year Grant For an injured axon to regrow, it needs to replace its leading edge, a structure called the growth cone. Scientists long believed that axons could not make the proteins needed to form a new growth cone but relied instead on proteins made in the cell body and shipped out to the axon. However, researchers know now that axons can manufacture the proteins. In fact, Dr. Twiss, a leading expert on protein synthesis in regenerating axons, has found that adult axons have the potential to synthesize a complex population of more than 200 different proteins. Dr. Twiss and his colleagues also have demonstrated that an injury triggers local protein synthesis in adult neurons that is especially robust in regenerating axons. Local synthesis enables axons to respond to their environment and supplies the regenerating nerves with a renewable source of components important for spurring and sustaining growth. If this mechanism could be harnessed, then scientists might improve the regenerative capacity of axons in the adult nervous system. Dr. Twiss now will try to identify how mRNAs, the templates required for generating proteins, are directed into and translated within axons. He hypothesizes that axonal mRNA transport and local synthesis sculpts the protein makeup of the axon and encourages growth. In this two-part study, the Twiss team will conduct both in vitro and in vivo experiments to determine precisely what cellular mechanisms send mRNAs into axons. In the second phase, Dr. Twiss will determine how an mRNA binding protein called La/SSB regulates the proteins manufactured in axons. If these experiments reveal increasing the mRNAs in the axon and enhancing their translation into protein improves the regeneration of axons, then the approach could lead to treatments for spinal cord injuries. Xie, Fang, M.D., Ph.D., University of California at San Diego, La Jolla, CA $120,000.00, 2-year Grant Myelin is the fatty layer that cloaks axons in the brain and spinal cord and enables them to fire effectively. However, the myelin that is so important for normal neurological function contains elements that prevent injured axons from regenerating. When scientists learned that the three major inhibitory proteins in myelin --Nogo, MAG, and OMgp-- had a common receptor called NgR1, they saw a promising target for treatments. Unfortunately, recent mouse models bred without NgR1 did not recover from spinal cord injuries dramatically better than normal mice. Researchers now believe that NgR1 alone does not account for the lack of axon regeneration, and the mechanisms that activate the anti-growth properties of myelin are complex. For example NgR1 is not present in all the neurons in the adult central nervous system. Furthermore, scientists have identified two close relatives of NGR1 --NGR2 and NgR3-- whose role is not thoroughly understood. Because NgR2 appears to bind with MAG and activate its anti-growth properties, this family of receptors may have overlapping roles. In this study, Dr. Xie, will use sophisticated genetic tools to explore the actions of these receptors, alone and in various combinations, both in cell culture and in mouse models. Dr. Xie’s laboratory already has bred mice without NgR1 and is in the final stages of generating a mouse in which NgR2 can be silenced. For this project, she will develop a mouse in which she can turn off its NgR3 so she can analyze the effect NgR3 on recovery and axon regeneration following a spinal cord injury. Finally, she will try to determine the how much redundancy exists among the NgRs in suppressing axon regeneration. She will conduct in vitro and in vivo studies with mouse models that she will develop that lack all three of the NgR receptors. Taken together, these studies should give scientists a far more detailed picture of the molecular interactions that give myelin its potent anti-growth properties. Yong, Wee V., Ph.D., University of Calgary, Calgary, Canada $62,500.00, 1-year Grant The acne medication minocycline, part of the tetracycline family, protects neurons that survive a spinal cord injury and improves the recovery of function in animal models of spinal cord injury. Based on Dr. Wong’s research, a human clinical trial is underway at the University of Calgary to test minocycline in treating spinal cord injuries. Meanwhile, he and his colleagues are investigating whether minocycline might be combined with other therapeutic drugs approved for human use. This criterion for testing available medications is important because, if a drug proves to be effective in animal experiments, it could quickly move to human trials. Dr. Wong has been testing glatiramer acetate, a drug used to treat multiple sclerosis, the disease that attacks the myelin coating that surrounds axons and enables them to function. The researchers have tantalizing evidence that this drug might also complement minocycline. They have found that the combination of minocycline and glatiramer acetate improved the recovery of animals afflicted with a multiple sclerosis-like disease. Furthermore, when researchers treated animal models of a demyelinating spinal cord injury with glatiramer acetate, the drug increased the number of oligodendrocyte precursor cells, early versions of the cells that produce myelin. Glatiramer acetate also has protected neurons in animal models of other neurological conditions, including Amyotrophic Lateral Sclerosis (ALS) and brain trauma. In this project, Dr. Yong will test glatiramer acetate alone and in combination with minocycline, on animal models to see if it improves recovery from spinal cord injury. If glatiramer acetate lives up to its promise, then it soon cold be tested in people. |