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2007 Grants Recipients
In the second of two cycles of 2007, the Christopher and Dana Reeve Foundation awarded over a million dollars in research grants -- that's over a million dollars in HOPE for people living with a spinal cord injury. With these grants, we are supporting the most brilliant-minded, skilled and experienced researches in fields such as immunology, neuroscience and molecular biology. Our funding provides the means for researchers to use knowledge and state-of-the-art technology to find desperately-needed answers. Not only will their findings impact how we treat and prevent spinal cord injuries, but also they can impact other devastating diseases such as Parkinson's, Alzheimer's, and Multiple Sclerosis. The laboratories and scientists funded in this cycle are located around the globe, and their projects span the entire research continuum from basic cellular and molecular-level laboratory work to clinical application in human patients. A complete list of project is below. We created short, easy-to-read summaries. And just in case here's our glossary of terms.
Myelin repair after spinal cord injury Building Somatosensory Circuitry Use of Tongue Movements as a Substitute for Arm/Hand Functions in Quadriplegics EphA4 in spinal cord injury and repair Autonomic standards for the evaluation of individuals with spinal cord injury (SCI) PPAR agonist treatment for spinal cord injury Modulation of BDNF expression in motor neurons to promote recovery of hand/digits motor functions in a rat model of rubrospinal tract injury Functional electrical therapy for restoring voluntary grasping in spinal cord injured patients The impact of autonomic dysreflexia on SCI patient skin and its role in skin ulcer formation Inflammation-associated factors that support neuroplasticity in chronic spinal cord injury Designer PGs for spinal cord injury Dietary restriction for spinal cord injury Regulation of intrinsic neuronal growth capacity by BMP and WNT signaling during axon regeneration Myelin repair after spinal cord injury Promotion of Axon Growth and Remyelination Casaccia-Bonnefil, Patrizia, M.D, Ph.D. Dr. Casaccia-Bonnefil studies how cells are born and die in the nervous system, particularly oligodendrocytes, the myelin-forming cells in the central nervous system. In this proposal, she will apply her expertise to spinal cord injuries. She will first try to prevent the cells that survive the initial injury from succumbing to a secondary wave of cell death that greatly expands the damage. She plans to test pifithrin alpha, a pharmacological compound known to block a "killer" protein called p53. Concentration of p53 increases near the spinal lesion as more and more cells die. In animal models, this drug yielded dramatic results, protecting the animals from toxins that normally kill oligodendrocytes and damage myelin. Next Dr. Casaccia-Bonnefil and her colleagues will explore how the molecular mechanisms responsible for the generation of new myelin might be recruited in the injured spinal cord. In previous studies, they found that molecules called histone deacetylases (HDACs) played a critical role during development in prodding progenitor cells in the brain to evolve into oligodendrocytes. These researchers also have identified a gene that is critical to the function of HDACs. In injury models in animals bred without the YY1 gene in the myelin-forming cells, their spinal cord axons had almost no myelin surrounding them. Researchers also found an increase in astrocytes, the cells that form scars and can interfere with axon regeneration. Dr. Casaccia-Bonnefil wants to determine which molecular networks YYI influences in oligodendrocytes, both during development and after spinal cord injury. The results of these experiments could lead to a combination therapy for spinal cord injury designed to protect the oligodendrocytes that survive the initial trauma, promote the generation of replacements for those that do not, and suppress the production of cells that can interfere with axon replacement. Building Somatosensory Circuitry Dodd, Jane, Ph.D. Sensory information that pinprick hurts! the silk is smooth travels from our extremities to the brain via the neurons of the somatosensory system. These sensory neurons lie in the dorsal horn of the spinal cord and carry information about the quality, intensity, and position of individual sensations to other segments of the spinal cord and to specialized centers in the brain, notably the cerebellum and thalamus. These centers process and integrate these messages. The somatosensory system accurately handles countless sensations from both our right and left sides and relays this information to both sides of the brain. When the spinal cord is damaged, people lose not only muscle function but also sensation and the coordination between sensory perceptions and the muscles that that were controlled by the somatosensory system. In addition, injury to somatosensory neurons can cause altered sensations, such as chronic pain. To repair this damage, scientists must first understand both the signals and mechanisms that generate this complex circuitry during embryonic development and the relationship between the arrangement of the circuits and their proper function. In this study, Dr. Dodd will focus on the evolution of one subset of spinal relay neurons called the D1 subpopulation. She already has generated important data on these neurons, which seem to be involved in sensing pain and the position of our arms and legs. She and her research team identified two genes that are normally activated in D1 neurons and showed that these genes play key roles in guiding D1 axons to their final destination. Dr. Dodd is hopeful that by manipulating these genes, she can alter the pathway and targets of D1 neurons. She will first trace the D1 circuitry as it develops and then will try to precisely what specific neurons do and selectively deactivate them in an otherwise normal animal model. She predicts that this approach will show how an individual circuit forms and functions and how changes in one isolated circuit affect the establishment of others and the way they interact to transmit information. Her findings could be critical to rebuilding the somatosensory system after an injury and eliminating the chronic pain that often plagues people living damaged spinal cords. Primary sensory afferent plasticity in a cauda equina/conus medullaris spinal cord injury and repair model in rats Havton, Leif A, M.D, Ph.D. Twenty percent of spinal cord injuries are to the lowest portion of the spinal cord. This section extends beyond the vertebrae and is called the cauda equina because it resembles a the tail of a horse. Damage to the cauda equina and the roots of the major nerves that lead away from the lower spinal cord may cause paralysis and numbness in the legs; bladder, bowel and sexual dysfunction; and chronic pain. Yet very little research has been In this project, Dr. Havton will delve further into how nerve pain develops and will look at how sensory nerve circuits reorganize in the twelve weeks following the injury. He suspects that pain is linked to the degeneration of the nerves that send sensory signals to the spinal cord and the subsequent death of sensory neurons in the dorsal root ganglia (DRG). This bundle of nerve tissue lies just outside the spinal cord, contains the cell bodies of the axons that transmit pain and other sensations from the body to the spinal cord. Dr. Havton has found that the number of inflammatory cells increases in the portion of the spinal cord that receives and processes pain signals from DRG neurons. This discovery could explain the etiology of chronic pain following the injury. Dr. Havton and his team will also test a surgical repair that has shown promise in his earlier experiments. The approach involves re-implanting the detached nerve roots into the spinal cord, which seems to protect neurons that survive the initial injury but would normally die in a second cascade of cell damage that follows a spinal cord injury. The surgery also spurs new axons to grow from within the spinal cord into the implanted nerve roots, reduces pain and inflammation, and promotes the recovery of bladder function. This technique might one day be used on patients with injuries to the lower spinal cord.
Ghovanloo, Maysam, Ph.D. When asked in a recent survey what change would most improve their lives, many quadriplegics ranked the restoration of their arm and hand functions above regaining the ability to walk. This grant will support the development of a highly promising assistive technology that Dr. Ghovanloo, an electrical engineer, predicts will be a viable substitute for some important arm and hand motions. Called the Tongue Drive System (TDS), this technology could one day enable people use tongue movements to operate a motorized wheelchair, work on a computer, dial a telephone number, and much more. TDS combines miniaturized electronic elements with existing wireless technology like Bluetooth® and is relatively inexpensive and minimally invasive. The tongue is ideal for this purpose because it makes precise, sophisticated movements with little exertion and, in effect, can perform like a joystick or computer mouse. Dr. Ghovanloo's invention has three main components: 1) a magnet the size of grain of rice that is coated in gold or platinum and either implanted in the tongue or secured to it by piercing; 2) tiny magnetic sensors arrayed along a dental retainer or on an external headset; 3) a coin-sized, sealed control unit that sits under the tongue, runs on a pair of watch batteries, and picks up signals from the sensors. Dr. Ghovanloo's team has written software to decode the signals, translate them to user commands, and then communicate the commands to a personal assistive device or computer. The principal advantage of TDS over other assistive technologies is that it can capture an unlimited number of tongue movements, and it can be customized based on each user's oral anatomy, remaining abilities, and preferences. Each tongue movement can be a specific command. As part of this research, Dr. Ghovanloo also will assess the efficacy and practicality of TDS as well as users' reaction to it. In addition, he will evaluate routines performed by users under the supervision of rehabilitation professionals at the WakeMed Rehab Hospital in Raleigh, NC. If this technology lives up to expectations, then it would offer severely disabled people much more control over their environment and the ability to work, making them less reliant on family members or other caregivers.
Herrmann, Julia Elaine, Ph.D. One reason that the spinal cord does not repair itself after an injury is that even when damaged neurons manage to sprout new axons, they cannot get past the scar that forms around the injured area. A protein that might be responsible for repelling new axons is EphA4. During embryonic development, EphA4 is a receptor for a signal molecule that repulses axons so that they stay on track toward their final destination in the central nervous system. Other researchers have found evidence that EphA4 may also restrict axon regeneration in the adult spinal cord after an injury. Dr. Herrmann, a post-doctoral fellow, wants to explore how this mechanism might work. Among the questions that she hopes to answer in this project are these: What axonal pathways and what cell-to-cell interactions does EphA4 influence at the injury site? If EphA4 is eliminated or deactivated, do animal models of spinal cord injury recover more function that they would otherwise? Could EphA4 exert a detrimental affect on one cell type but a beneficial one on another? To answer these questions, Dr. Hermann plans to run a series of experiments, both in cell cultures and on mouse models of spinal cord injury. First she will delete EphA4 entirely and see what happens. Then she will develop a system for deleting EphA4 in different cell types one at a time so she can determine precisely how and when the receptor comes into play. Understanding exactly how EphA4 works is a crucial first step in determining whether it may be a target for the treatment of spinal cord injuries. Autonomic standards for the evaluation of individuals with spinal cord injury (SCI) Krassioukov, Andrei V., M.D, Ph.D. Most research on the effects of spinal cord injuries and possible treatments focuses on voluntary movements, like walking and standing, and on the somatic nervous system that receives and processes sensory information from the periphery of the body. However, spinal cord injuries also disrupt the complex autonomic nervous system, which controls involuntary functions like blood pressure, heart rate, and digestion. In fact, the autonomic nervous system influences nearly every function in the body, and they all can become erratic when the spinal cord is damaged. Until recently, scant attention was paid to these problems, some of which can pose life-threatening complications. As a result, scientists and physicians have limited understanding of autonomic dysfunction, no accepted definition for it, and few treatments or rehabilitation regimens to offer patients. Nor does any standard battery of tests exist to assess and monitor autonomic functions in the spinal cord injured. Certainly doctors can measure, say blood pressure and temperature, but most of these tests were developed and standardized for the able-bodied or people with other autonomic disorders. So it is difficult to select appropriate tests for people with spinal cord injuries. Dr. Krassioukov, a noted expert in autonomic dysfunction, hopes to fill these gaps. This grant will help to support a collaborative international effort to develop a comprehensive, reliable battery of tests, tailored to the spinal cord injured population. Once validated, these tests will be used to evaluate autonomic dysfunction in patients during the acute phase of their injury and long afterward. These tests would also be important in clinical trials of drug treatments and exercise routines. Dr. Krassioukov and other specialists in this field already have selected the tests most likely to be useful in individuals with spinal cord injuries. Now clinicians in Vancouver, B.C.; Toronto; and Louisville will evaluate the reliability of these assessment tools. Once the combination is validated, it could have a major impact on the care and quality of life of people with spinal cord injures.
McTigue, Dana , Ph.D. Following a spinal cord injury, the body unleashes a full-blown immune response that helps to fight infection. Microglia and macrophages, two types of immune scavenger cells, amass at the injury site to clean up cellular debris, but they also release molecules that cause inflammation, which is toxic to nearby surviving cells. As more cells die, the cycle continues, creating a second cascade of cell death and increasing the loss of function. Based on evidence from other researchers, Dr. McTigue predicts that if the pro-inflammatory products released by the immune cells could be limited, then secondary cell death would be reduced. In this study, she will test two drugs that have been shown to decrease dramatically the negative effects of inflammation and to protect surviving neurons. The first is the diabetes drug, Pioglitazone, which is now being tested in patients with multiple sclerosis. Pioglitazone activates PPARg, a protein in the nucleus of microglia and macrophages that triggers a mechanism that curbs the production of potentially harmful molecules. This drug protects brain and spinal cord cells in models of Amyotrophic Lateral Sclerosis (Lou Gehrig's disease), Parkinson's disease, Alzheimer's disease, and multiple sclerosis. Dr. McTigue has demonstrated that injecting Pioglitazone into rat models of spinal cord injury preserves spinal cord tissue and improves the animals' recovery of function. The second drug to be tested, Ibuprofen, has received increased attention among researchers for its possible role in preventing or delaying Alzheimer's disease. Ibuprofen is thought to stimulate PPARg pathways, which in turn decrease inflammatory functions in microglia and macrophages. Dr. McTigue plans to test oral Pioglitazone in a rat model of SCI and then combine Pioglitazone with Ibuprofen to determine if the dual treatment is better than giving either drug alone. One recent study found that the combination was more effective in an animal model of Alzheimer's disease. Using rat models, Dr. McTigue will assess the effect of these drugs on pain, the ability to walk, and the recovery of normal sensory function. If her results are encouraging, human trials could follow relatively quickly because both drugs already are known to be safe and are widely used. Modulation of BDNF expression in motor neurons to promote recovery of hand/digits motor functions in a rat model of rubrospinal tract injury Morris, Renée , Ph.D. Scientists have known for some time that neurotrophins, proteins that help neurons to survive, can promote the growth of new axons following a spinal cord injury. In animal tests of treatments for spinal cord injuries, the state-of-the-art approach is to transplant into the spinal lesion cells that have been genetically modified to secrete neurotrophins. Unfortunately, this once-promising technique has failed to produce axon growth beyond the area where the engineered cells are introduced. What stops the regenerating axons from leaving? Dr. Morris hypothesizes that the axons remain where they like the "neighborhood." To reach their target connections in motor neurons, new axons would have to abandon a rich source of neurotrophins and head into a poorer environment. In this experiment, Dr. Morris hopes to lure axons to where they need to be by systematically increasing levels of the neurotrophin BDNF along their path. In other words, by offering them rewards along the way, Dr. Morris believes axons will elongate far enough to re-establish lost nerve circuitry and restore function. To introduce BDNF at the right time and place, Dr. Morris will rely on the intra-nerve transport system. This mechanism allows nerve endings in the muscles to take up foreign agents large proteins, viruses, and even metal particles, for example and push them through the peripheral nerves toward the spinal cord. In theory, this retrograde transport system could move BDNF toward the spinal cord. Dr. Morris plans to test this approach on rodent models of an injury to the cervical spinal cord that paralyzes the animals' forepaws. She will use a deactivated virus that has been modified to carry the gene for BDNF and introduce the virus in a series of carefully targeted intramuscular injections. The first injection will go into the shoulder to produce high levels of neurotrophins close to the injury in order to sustain injured neurons and to spur them to sprout new axons. Subsequent injections in the upper and then the lower parts of the forelimb will gradually shift the concentrations of BDNF downward, attracting the elongating axons toward the motor neurons, further from the lesion, to make functional connections. The animals' recovery will be assessed with sensitive tests of their ability to use their paws and digits. If Dr. Morris is successful, her technique might offer be an important step in repairing the spinal cord, between prodding neurons to replace their injured axons and having those new axons grow long enough to reconnect damaged nerve circuits and restore lost function. Functional electrical therapy for restoring voluntary grasping in spinal cord injured patients Popovic, Milos R., Ph.D. Dr. Popovic applies his background in mechanical and electrical engineering to improving rehabilitation regimes for people who have suffered paralyzing strokes and spinal cord injuries. In this project, he will build on his preliminary studies that show that a new application of functional electrical stimulation (FES) may enable quadriplegics to regain some use of their hands. The approach also seems to be useful for stroke patients. In FES, a Walkman-sized transmitter is used to deliver electrical stimulation to specific nerves that in turn enable patients to open their hands or move their feet. In traditional rehabilitation programs, FES is incorporated into permanent assistive devices that users rely on to accomplish simple everyday tasks. Dr. Popovic has shown that FES also can be used as short-term therapy to help people with incomplete spinal cord injuries to recover voluntary grasping function. He hypothesizes that once participants complete this therapy, they should be able to grasp objects without the artificial stimulation. In this study, Dr. Popovic and his team will investigate whether a series of orchestrated FES treatments can retrain the voluntary grasping function in individuals with new spinal cord injuries and compare this technique to conventional occupational therapy. He plans to recruit 64 participants with incomplete quadriplegia who can generate only weak wrist and finger movements. Half will receive the enhanced, short-term FES treatment; the other half will complete conventional occupational therapy of equal intensity. A researcher who will not know to which treatment groups the participants are assigned assess their hand function before and after treatment and will rank their level of independence. This new approach promises to be a low cost intervention that might one day enable people with high-level spinal cord injuries to live more independently. The impact of autonomic dysreflexia on SCI patient skin and its role in skin ulcer formation Ramella Roman, Jessica , Ph.D.
Shine, Harold David, Ph.D. The spinal cord is complete severed in only a third of patients with cord injuries, so treatments that enhance the function of the surviving nerve circuitry could provide limited but significant improvement in the their prognosis. In preliminary tests on rat models of incomplete spinal cord injuries, Dr. Shine could prod surviving neurons to make new axons with experimental gene therapy, provided that it was given soon after the injury. When he gave the same therapy four months after the injury, it had no effect. The treatment to increased levels of Neurotrophin-3 (NT-3) in the spinal neurons of the animals. NT-3 is one of the natural occurring proteins in the brain and spinal cord that work like neuron fertilizer, fostering their growth and survival. In more recent studies, Dr. Shine found evidence that the immune response to the injury, which causes inflammation and promotes healing, somehow enhanced the effect of the NT-3. When he and his team induced a system-wide inflammation in rats with older spinal cord injuries, the NT-3 gene therapy worked well. Now Dr. Shine plans to pinpoint precisely how the inflammatory response to injury enhances the effect of the NT-3 so that surviving axons grow in the chronically injured spinal cord. Once he has identified the actor or actors in this process, he will deliver their genes along with the NT-3 gene in his experiments on rats with older injuries. Identification of this "second signal" could be a first step toward trials of a gene therapy for humans with incomplete spinal cord injuries.
Snow, Diane Michelle, Ph.D. Although the scar that forms following a spinal cord injury is beneficial for the recovering nervous system and should not be removed, it contains substances that prevent new axons from growing. The spinal cord might regenerate following an injury, if the growth inhibitors in the scar could be kept from the scene or deactivated when they arrive. Chondroitin sulfate proteoglycans (CSPGs) are one of these inhibitory agents. These large molecules occur naturally in the extracellular matrix, and they arrive at the injury sight wthin hours and stay for several months. The goal of this project is first to identify the most potent growth inhibitors in CSPGs and then to manipulate them so that they can no longer block axon regeneration. To this end, Dr. Snow and her collaborators have engineered an array of CSPGs and mutant CSPGs that vary slightly from one another. They also have devised a variety of techniques to study these so-called designer CSPGs in the laboratory. These include a novel model of the glial scar as well as imaging methods to measure subtle features of neuron responses to CSPGs. With these tools, Dr. Snow and her team will try to pinpoint and then manipulate the specific inhibitory parts of CSPGs and assess the effects of these interventions on axon regeneration in vitro. Once the most potent inhibitors are identified, she plans to test whether the techniques that neutralize them in the laboratory will promote regeneration in animal studies. These experiments could some day translate into treatments that would enable the injured human spinal cord to rebuild itself.
Shenoy, Krishna Vaughn, Ph.D. When traditional medical treatments fail or do not exist to cure diseases or repair injuries. Bioengineers increasingly are filling the void Electronic medical systems that interface with the nervous system, termed neural prosthetic systems, have started to offer promising solutions to people with previously intractable conditions. Successes include cochlear implants, invented 25 years ago for the profoundly deaf, and deep brain stimulators to alleviate tremor associated with Parkinson's disease, which have been used for the last decade. Dr. Shenoy is part of a renowned group of neuroengineers who have been developing prosthetic arm and communication systems. These systems, which are also referred to as brain-computer or brain-machine interfaces, aim to give people control of paralyzed or prosthetic arms, computers, and machines. These motor and communication systems translate electrical impulses from the brain into control signals for guiding prostheses. Dr. Shenoy's laboratory and other researchers already have shown that monkeys and humans can learn to move computer cursors and robotic arms to various target locations simply by activating the neural circuitry that normally would control natural arm movements. Although these experimental systems offered compelling, headline-grabbing proof that brain-computer interfaces work, they fall far short of enabling users to complete such ordinary tasks as reaching straight for a glass of water or typing words rapidly on a keyboard. Under this three-part project, Dr. Shenoy and his team will try to mimic more closely the how the brain works in order to improve the performance of monkeys using cortically-controlled prosthetic arms and cursors. In the first experiment, they will design new algorithms step-by-step instructions that become computer programs to capture the distinct way the brain functions when used to control external devices rapidly. In the second, they will try to create new algorithms that take into account differences between natural and prosthetic arms with respect to where objects that must be reached or touched are placed. The precise location of, say, a joystick or a spoon matters little to someone with normal arm function. But to someone with a prosthetic arm controlled by individual neurons in the brain, unavoidable "sampling biases" result in some regions of space being better than others. Again we will design novel algorithms and demonstrate their performance benefits. Finally, these researchers will try to improve the ability of a prosthetic device to distinguish when someone is merely thinking about executing a move from actually wanting to do it. Together these experiments, computations, and theoretical advances could considerably result in far more sophisticated and responsive prostheses.
Streijger, Femke , Ph.D. High-caloric intravenous or tube feedings are part of the acute care of routinely given to people with new spinal cord injuries. This young researcher notes, however, that this practice has never been rigorously tested and patients may actually require far fewer calories because of inactivity and spinal shock. Dr. Streijger is part of a research group that has been testing an opposite approach: dietary restriction, in the form of every other day fasting (EODF). In experiments with rat models of incomplete crush injuries to the cervical spinal cord, these researchers have discovered that rats fed only every day had dramatic advantages of the control animals. The experimental animals had lesion cavities half the size of those in the control animals, more surviving nerve cells in the vicinity of the injury, and enhanced growth of the nerve used in fine motor function. Most importantly, the rats on the fasting routine recovered more limb function and regained a more normal walking pattern. These experiments were the first to demonstrate that dietary restriction is beneficial as a treatment for spinal cord injuries in animals. In this project, Dr. Strijger will run a series of experiments she hopes will provide the data needed to move this promising approach into human clinical trials. She will test every-other-day fasting on a rat model of a contusion injury to the cervical spinal cord, a more common type of injury in humans, and will try to determine how long this regimen has to be maintained to be effective. She also will explore whether alternate-day fasting has any benefits with older injuries. To validate this intervention in a second species, she will test the fasting regimen on mouse models. Because the mouse genome has been deciphered, she can begin to look for which genes are involved in the response to caloric restrictions. Her long-term goal is to explore the molecular mechanisms that underlie the beneficial effects of caloric restrictions in spinal cord injuries. As a first step, she will analyze how fasting affects spinal cord and general organ inflammation. If these experiments provide additional support for dietary restrictions, they could lead to a non-invasive, inexpensive, and highly effective treatment for acute spinal cord injuries.
Zhou, Fengquan , Ph.D. Nerves in the periphery of the body can regrow following an injury, but those in the central nervous system cannot. Scientists are trying to learn just how peripheral axons manage to repair themselves in hopes that the mechanism can be harnessed to repair damage in the brain and spinal cord. One way to study periphery regeneration is to look at dorsal root ganglion (DRG) neurons that lie just outside the spinal cord. They have two axons, one that carries sensory information from the periphery to the cell body and another that transmits the information from the cell body to the spinal cord. Scientists know that an injury to the periphery axon of a DRG neuron enables its partner axon to regrow if it is subsequently injured. Dr. Zhou has found that the first, so-called conditioning injury to a periphery axon makes the other axon more responsive to growth-promoting substances called neurotrophins. Treated axons are able to extend long distances, despite exposure to potent growth inhibitors that are present in the injured spinal cord. He has also discovered that the conditioning injury turns off a molecular stop signal that otherwise would prevent axon regeneration and activates certain go or growth signals. Under this grant, Dr. Zhou will run a series of experiments that he hopes will reveal precisely how the conditioning injury triggers these signaling changes. He will then try to mimick those changes by using gene therapy to see if axons will regrow in mouse models of spinal cord injuries. |
Use of Tongue Movements as a Substitute for Arm/Hand Functions in Quadriplegics
EphA4 in spinal cord injury and repair
PPAR agonist treatment for spinal cord injury
Inflammation-associated factors that support neuroplasticity in chronic spinal cord injury
Designer PGs for spinal cord injury