2003 Second Cycle Research Grant Recipients
$1,811,134.00
Appel, Bruce, Ph.D., Vanderbilt University, Nashville, TN
$75,000.00, 1-year Grant
Analysis of Oliogodendrocyte precursor migration in zebrafish
Research category: Promotion of axon growth and remyelination
Dr. Appel and his team are studying how oligodendrocytes myelinate new axons. During embryonic development, spinal cord oligodendrocytes arise from the ventral (or stomach) side of the spinal cord and travel to new positions in the dorsal (or back) side. These researchers want to know precisely how those newborn oligodendrocytes reach their target neurons. Dr. Appel has developed a genetically engineered zebrafish, a unique model that enables scientists to watch oligodendrocytes migrate in real time. The zebrafish embryo is a good model because it is transparent and has relatively few oligodendrocytes. Dr. Appel has bred his zebrafish with a jellyfish gene that produces a glowing, neon green protein in the precursor cells of both the ventral neurons and the oligodendrocytes, so he can see how oligodendrocytes migrate and rendezvous with their target neurons. In this two-part project, Dr. Appel will explore the role of netrins, signaling molecules that guide developing axons to their final destinations. Next, he will breed zebrafish with certain mutations to try to identify other factors that influence oligodendrocyte migration. Understanding this early process may help scientists to restart myelination as part of the treatment for spinal cord injuries and demyelinating diseases.
Carmena, Jose M., Ph.D., Duke University Medical Center, Durham, NC
$120,000.00, 2-year Grant
Closed-loop brain-controlled prosthesis for recovery of upper-limb functionality in subjects with spinal cord injuries.
Research category: Rehabilitation
Dr. Carmena is part of a team at Duke University that has dramatic evidence that trained monkeys can guide a robotic arm with their thoughts. The researchers implant electrodes into the parts of the animals' brains that control motor activity and then capture the electrical impulses that neurons send to the arms and hands. These signals then are analyzed and converted into instructions for the robot. The approach relies on a computerized system known as a closed-loop brain-machine interface that connects the electrodes in the monkeys' brains to a computer-driven mechanical arm. Duke researchers recently have shown that animals, viewing their progress on a computer screen, can change the position and gripping force of the arm with their brain waves. Duke researchers spent more than two years recording brain activity from hundreds of sites in the brains of macaque monkeys while the animals used their arms in a variety of activities and games. Eventually, the researchers could discern patterns that were associated with reaching, grasping, and manipulating objects in space. In this study, Dr. Carmena will continue to gather evidence that the electrodes can remain in place for long periods of time without harming the monkeys and that the animals can learn to master increasingly complex maneuvers, such as feeding themselves. This exciting work could lead to a brain-controlled upper-limb prosthesis that might one day enable people with high-level spinal cord injuries to recover the use of their arms.
Clemens, Stefan, Ph.D., Emory University, Atlanta, GA
$67,859.00, 1-year Grant
Dopaminergic control of spinal cord function
Research category: Concomitant function
Dr. Clemens wants to understand what happens when a spinal cord injury disrupts nerve pathways that control the sympathetic nervous system. This system governs a range of involuntary functions in the body, including blood pressure, heart rate, digestion, and the fight-or-flight response to stress. In this study, he will explore the nerve fibers that are influenced by dopamine, a neurotransmitter that the brain needs to control movement, emotional responses, and the ability to experience pleasure and pain. Dopamine helps to regulate of the sympathetic nervous system. People with spinal cord injuries often have markedly overactive sympathetic nervous systems, causing serious medical problems. These include dangerous spikes in blood pressure, bowel and bladder problems, and sexual dysfunction. Dr. Clemens and his team will explore how dopamine influences the excitability of the nerve cells that lead to smooth muscles in glands, internal organs, and blood vessels. These researchers also will determine whether heightened activity in the sympathetic nervous system affects the nerve fibers that carry pain signals from the muscles to the spinal cord and, if so, how exactly this action occurs. These findings could be particularly important because researchers might then test whether dopamine therapy, which is used to treat patients with Parkinson's disease and restless leg syndrome, might reduce some serious complications in people with spinal cord injuries.
Cosman, Felicia, M.D., Helen Hayes Hospital, West Haverstraw, NY
$149,616.00, 2-year Grant
Acute spinal cord injury: a randomized controlled trial to prevent bone loss.
Research category: Concomitant function
In the first year after they suffer a spinal cord injury, men and women can lose fifteen percent or more of their bone mass, particularly in their pelvis and legs. Elevated blood proteins reflect this rapid dissolution of bone, which invariably leads to osteoporosis. As a result, many people with spinal cord injuries often break bones, not only when they fall but also, tragically, during the course of normal activities. These fractures can be painful, slow to heal, and cause further disability; and they require medical and sometimes surgical treatment. People with spinal cord injuries suffer more complications than people do who have osteoporosis alone. No treatment exists to prevent or treat osteoporosis in the spinal cord injured. Some therapies, including electrical stimulation and passive weight bearing, have limited success. Certain bone-preserving medications also appear to help, but none has been subjected to a rigorous randomized and controlled study. In this project, Dr. Cosman will test the effectiveness of a single dose of zoledronic acid, a potent medication that inhibits the resorption of bone. Doctors use zoledronic acid, which must be delivered intravenously, to treat cancers that invade the bones. The drug has also been used experimentally to counter osteoporosis in post-menopausal women. Dr. Cosman will administer the drug within 10 weeks of injury to patients while they are still receiving inpatient rehabilitation. She will monitor bone dissolution with blood and urine tests and bone density with noninvasive scans. These tests will begin while the patients are hospitalized and continue during routine outpatient follow-up visits. If this treatment prevents osteoporosis and its complications, it could greatly improve quality of life for people with spinal cord injuries and keep them strong enough to benefit from future treatments that might restore their mobility.
Darian-Smith, Corinna, Ph.D., Stanford University School of Medicine, Stanford, CA
$74,756.00, 1-year Grant
Cervical dorsal root lesions in monkey: impairment of dexterity and plasticity of primary sensory neurons
Research category: Rehabilitation
Dr. Darian-Smith has developed a primate model of a cervical dorsal root injury that occurs relatively often in human beings during traumatic births and accidents involving impact. The cervical dorsal root is the juncture of sensory nerves from the arm and hand and the spinal cord. Damage to these nerve fibers greatly impairs manual dexterity and may cause permanent loss of arm and hand function. Less severe dorsal root injuries affect fine motor skills. In earlier studies, Dr. Darian-Smith found that when all the dorsal rootlets that activate the thumb or index finger are cut, the animals could not hold objects between these two digits because they no longer sent sensory feedback to the brain's cerebral cortex. Within a few months, however, the primates showed significant – but still incomplete – recovery of their hand function and a return of activity in the corresponding region of the brain, even though the severed nerve cells did not regenerate. Dr. Darian-Smith credits the recovery to intact sensory nerve cells that supply the thumb and index fingers through dorsal rootlets adjacent to the injury. She hypothesizes that these rootlets are either too sparse or make too few connections (or both) to be useful immediately after the injury. Later, however, these intact central nerve fibers begin to sprout new axons. In this project, Dr. Darian-Smith will examine how the peripheral nervous system of the animals adjusts after their dorsal roots are cut that transmit tactile information from the thumb and index finger. Her results will show whether behavioral and anatomical improvements can be traced to new connections between nerve cells and those in the spinal cord and brain stem that had lost input. Cells in more complex areas of the brain also undergo significant structural and functional reorganization following the interruption of cervical dorsal roots. Dr. Darian-Smith will explore these adaptations and correlate them with the impairment and possible recovery of manual dexterity. A better understanding of the ability of the nervous system to reshape itself following an injury is key to finding rehabilitation therapies to help people recover from disabling shoulder and arm injuries.
Ehlers, Michael D., M.D., Ph.D., Duke University Medical Center, Durham, NC
$150,000.00, 2-year Grant
Spatial regulation of endocytosis during growth cone migration and collapse
Research category: Axon guidance, synapse formation and neurotransmission
The growth cone, a complex structure at the tip of a developing axon, obeys signals in its environment to extend, turn, or retreat. These maneuvers enable the axon to arrive at its final stop in the nervous system. Dr. Ehlers believes that within the navigational tools of the growth cone, lie clues to why axons do not regenerate after an injury. The behavior of a growth cone depends on a precise arrangement of molecules on its surface. At the leading edge, are dynamic finger-like projections called filopodia, which are richly covered by sticky adhesion molecules and signaling receptors. In contrast, the rear of the cone is far less adhesive and has a different cast of receptors. This territorial division of labor is critical if the cone is to tug its axon forward and respond to the push and pull of guidance signals. One way a growth cone controls its surface composition is through endocytosis. This process draws receptors, along with the piece of cell membrane they occupy, into the interior of the growth cone and seals them off. By removing receptors, endocytosis alters the ability of the growth cone to respond to go-forward signals; by nabbing part of the membrane, it can trigger the collapse of the cone. In fact, when a growth cone encounters a growth-inhibiting environment – as it does when it tries to move through the scarred region of the injured spinal cord – it appears to rapidly devour its membrane and then collapse. Dr. Ehlers has been researching a protein molecule called clathrin, which coats the inside surface of the cell membrane and facilitates endocytosis. He has found that clathrin resides only on some parts of the growth cone and that it responds vigorously to growth-inhibiting proteins. He assumes, then, that a powerful relationship exists between endocytosis and the anti-growth signals that keep axons from regenerating. In this study, Dr. Ehlers will investigate this provocative possibility using live-cell fluorescence imaging techniques to watch growth cones in action. He plans to pinpoint where and when endocytosis occurs during axon pathfinding and how inhibitory molecules affect it. These studies will provide new insights into why injured neurons fail to replace their axons and how best to help growth cones to persevere through hostile territory and rebuild lost nerve circuits.
El Manira, Abdeljabbar, Ph.D., Karolinska Institutet, Stockholm, Sweden
$150,000.00, 2-year Grant
Awaking locomotor networks by activation of endogenous modulatory receptors
Research category: Rehabilitation
An injury cuts off the connections between the spinal cord circuits that control leg and foot muscles and the areas of the brain that normally activate them. Mounting evidence has shown, however, that other ways exist to turn on the nerve networks needed for walking. These approaches include the stimulation of certain receptors on the motor neurons, the nerve cells that produce muscle contractions. In this project, Dr. El Manira will explore how the neurotransmitter glutamate might activate spinal circuitry. Glutamate is released from spinal neurons and improves cell-to-cell transmission. Dr. El Manira will focus on one type of glutamate receptor that excites nerve cells. Using an in vitro model of the lamprey eel spinal cord, he will test how activation of this receptor increases the excitability of spinal circuits. If successful, this project could lead to treatments that combine drugs that activate glutamate receptors with locomotor training or other forms of rehabilitation to help people recover the ability to walk after spinal cord injuries.
Garcia, K. Christopher, Ph.D., Stanford University School of Medicine, Stanford, CA
$150,000.00, 2-year Grant
Structural biology of Nogo receptor-ligand interactions
Research category: Growth Inhibition
Dr. Garcia and his team recently mapped the three-dimensional structure of the Nogo receptor (NogoR). When activated, this key receptor launches a series of reactions that prevents neurons from replacing their axons after a spinal cord injury. Other researchers have demonstrated that inactivating NogoR permits injured neurons to grow replacement axons to restore nerve circuits that are disrupted by injury. In this study, Dr. Garcia will turn his attention to how NogoR interacts with its three signaling partners, or ligands, the inhibitory molecules called Nogo, Mag, and OmGP. These molecules are present in myelin, the fatty coating that surrounds axons. Dr. Garcia will combine cutting-edge techniques from physics and molecular biology to determine the exact positions of every atom in these molecules. He will produce highly detailed, three-dimensional images of these ligand-receptor complexes. The results will enhance scientists' basic understanding of receptor signaling in nerve cells and help researchers to design drugs that would change the "no-go" signals to go.
Grillner, Sten Erik, Ph.D., Karolinska Institutet, Stockholm, Sweden
$150,000.00, 2-year Grant
Mechanisms of modulation of the locomotor CPG - a synaptic, cellular and molecular analysis
Research category: Rehabilitation
Dr. Grillner was one of the first researchers to recognize thatthe spinal cord itself could be "taught" to activate the network of nerve cells that controls the muscles involved in walking. He and others have shown that animals that are paralyzed after a partial spinal cord lesion can recover their ability to walk after they undergo training in which they are helped to step on moving treadmills. Messages from the sensory nerves in the legs and feet activate the rhythmic firings of the so-called locomotor network. Based on these findings, locomotor training routines were developed that have helped some people regain limited walking. For example, they now can walk on flat surfaces using a walker or a cane. The critical element is that some of the fibers from the brainstem remain intact so that they can switch on the locomotor network. It is crucial that this network remain primed, or excited, so that even small input from the surviving fibers can properly activate it. In this study, Dr. Grillner and his team will use a lamprey eel model to study how neurotransmitters enable even feeble signals from the brain to activate the locomotor network. The results could lead to new drug therapies.
Gu, Chenghua, Ph.D., Johns Hopkins University School of Medicine, Baltimore, MD
$120,000.00, 1-year Grant
Semaphorin/neuropilin signaling during development and adult CNS regeneration
Research category: Axon guidance, synapse formation and neurotransmission
Researchers have recently identified several families of proteins that attract or repel developing axons, helping them to navigate toward their target connections. Dr. Gu is interested in how the powerful repellant proteins called Class 3 secreted semaphorins operate through a complex of receptors on the leading edge of the axon. In both in vitro and in vivo experiments, Dr. Gu will investigate how these receptors, called neuropilins and plexins, function during development and regeneration. She will first analyze precisely how Class 3 semaphorins interact with their receptors. Then, using four mouse models, each bred to lack a different neuropilin, she will examine how the absence of each one affects the developing nervous system. Finally, she will test whether the interactions between the Class 3 semaphorins and their neuropilin receptors prevent axons from regenerating in the mutant mice. These findings should further scientists' understanding of how repulsive guidance molecules operate during development and after injury.
Martin-Villalba, Ana, M.D., Deutsches Krebsforschungszentrum, Heidelberg, Germany
$150,000.00, 2-year Grant
Blocking of CD95-Ligand-Induced cell death to treat spinal cord injured patients
Research category: Neuroprotection
Under a previous grant from CRF, Dr. Martin-Villalba showed how, following a spinal cord injury, the concentration of a signaling molecule called CD95-ligand rises following a spinal cord injury. She also found that this ligand plays an important role in apoptosis, which causes cells to destroy themselves when they "sense" a disruption in their environment. By neutralizing the CD95-ligand, Dr. Martin-Villalba greatly reduced apoptotic cell death in animal models of spinal cord injury. Most importantly, the test animals that received the experimental treatment began to recover hind paw movements in four weeks while non-treated animals remained paralyzed. Disabling the CD95-ligand also promised to improve the survival of nerve cells and to preserve the myelin coating that protects axons. In this study, she will continue to explore how CD95-ligand magnifies the damage from a spinal cord injury. She also will try to determine the window of opportunity for silencing this signaling molecule to optimize the recovery of function in animal models. She also hopes to study how MRI imaging can be used to monitor the recovery of people with spinal cord injuries.
Sadowsky, Cristina Lavinia, M.D., Washington University in St. Louis, St. Louis, MO
$71,165.00, 1-year Grant
Effects of an Activity-Based Therapeutic Program on Physical Health and Quality of Life in Persons with spinal cord injuries
Research category: Rehabilitation
In this retrospective study, Dr. Sadowsky will assess the benefits of a rehabilitation program that adds three hours a week of functional electrically stimulated (FES) bicycling to a traditional regimen of stretching and strengthening exercises. In FES, electrical currents activate paralyzed leg muscles so subjects can pedal stationery bicycles. Dr. Sadowsky and her colleagues have observed that patients who trained on the bicycles for more than a year seemed to fare better, both physically and psychologically than those who did not. For example, patients who began the training in the first month following their injury did not need medications to control spasticity. Under this grant, she hopes to validate those observations by analyzing the medical histories of the cyclers and noncyclers. The two groups will be matched for the severity of their injury and the time that had elapsed between the injury and the start of therapy. In addition, she will run a prospective, one-year study to compare the health of two new groups of matched patients. She will asses their spasticity, muscle strength and mass, bone density, lipid and testosterone levels, physical and neurological function, and quality of life. The results of these two studies should help clarify the most effective forms of rehabilitation for spinal cord injuries.
Tuszynski, Mark H., M.D., Ph.D., University of California, San Diego, La Jolla, CA
$75,000.00, 1-year Grant
Nerve guidance channels for spinal cord injury
Research category: Cellular replacement and artificial substrates
With increasing frequency, researchers are including natural and synthetic nerve guidance channels in animal experiments that test potential treatments for spinal cord injuries. These channels serve several key functions. They can bridge the gap between injured nerve stumps, shelter regenerating axons from the damaging molecules that flood an injury site, guide and direct those new axons toward their targets, and release therapeutic substances that encourage the survival and regrowth of injured nerve cells. For this project, Dr. Tuszynski and his experienced team of spinal cord injury researchers will collaborate with scientists at the NASA Jet Propulsion Laboratory in Pasadena, who are experts in the field of fabricating miniature devices. Together these two groups will develop a novel type of nerve guidance channel from hyaluronic acid, which they will stabilize to maintain its shape and then perforate with tiny pores. Hyaluronic acid is a natural material found throughout the spinal cord that decreases scarring and provides a congenial environment for nerve cell regeneration. Dr. Tuszynski's laboratory will transplant the channels into rat models and, after one and three months, will track axon regeneration and the cellular response to the channels. This study could provide a useful new tool for helping axons to regrow.
Whittemore, Scott, Ph.D., University of Louisville, Louisville, KY
$150,000.00, 2-year Grant
Stem cell repair of spinal cord injury
Research category: Stem cells
Axons that survive a spinal cord injury still may shed their protective myelin sheath, which robs them of the ability to transmit nerve impulses. This demyelinization increases the loss of function from the original trauma. Dr. Whittemore and his team are trying to perfect a cell transplant technique that will deliver cells to the injured spinal cord that can replace lost myelin and restore function. In addition, these researchers have been testing better assessment tools so they can accurately determine whether the transplanted cells actually do improve neuron-to-neuron transmissions and alleviate paralysis. To that end, Dr. Whittmore has developed two animal models of injuries that demyelinate axons and create specific behavioral and electrophysiological deficits. His preliminary data show that after both models receive primitive cells known as glial-restricted precursors, the animals recovered partial function. Glial precursors evolve into the cells that support neurons, including oligodendrocytes, which manufacture myelin. In this study, Dr. Whittemore will try to optimize that recovery and explain why full recovery does or does not occur. He will genetically modify the precursor cells both to enhance their proliferation and their ability to evolve into oligodendrocytes. He will track the effects of each mechanism. In a second round of experiments, he will add other types of primitive cells as well as growth-promoting substances in hopes of further enhancing the recovery of function.
Wilson, Sara Ivy, Ph.D., Columbia University, New York, NY
$120,000.00, 2-year Grant
Spinal Commissural Neurons: Functional Development and Circuitry
Research category: Axon guidance, synapse formation and neurotransmission
To function properly, the body has to process accurately thousands of different sensory messages, like the texture of sandpaper, the position of an arm or leg in space, or the temperature of a child's forehead. This ability depends on intricately organized circuits assembled from many different types of neurons and synapses. When a spinal cord injury breaks these neural circuits, information no longer travels from the body to the brain and back again. To rebuild these pathways, researchers must understand how these circuits formed, how they sorted themselves into networks, and why proper function depends on that specific arrangement. In this three-part project, Dr. Wilson will use a type of commissural neuron that relays sensory information from one side of the body to the other. These neurons also play a role in coordination, pain perception, and touch. She first will modify the genes that are active in commissural neurons to try to manipulate their behavior. Second, using neurons that she will genetically engineer to emit a green flourescence, she will trace the formation a specific circuit. Finally, she will activate a toxin in these neurons, selectively killing them in an otherwise normal animal so she can assess how these changes affect the processing of sensory information. These experiments will reveal not only how an individual circuit forms and functions, but also how the manipulation of one isolated circuit can influence other circuits. This work will also clarify how neural circuits receive and interpret sensory information.
Xu, Xiaorong, Ph.D., University of Rochester, Rochester, NY
$97,738.00, 2-year Grant
Assuring conduction in spinal motor neurons
Research category: Promotion of axon growth and remyelination
In spinal cord injury, motor neurons that carry signals to muscles in arms and legs may be damaged or destroyed. Attempts to restore function often involve the transplantation of primitive cells that evolve and differentiate into motor neurons. Regardless of how they are introduced, the new neurons must mature in the damaged cord and gain the ability to generate and conduct electrical impulses to their target muscles. Neurons do not act alone, however. They need helper, or glial cells, to ensheathe them in a protective coating of myelin. And the neuron must be primed to fire properly. In this project, she will grow spinal motor neurons in a cell culture that will enable her to manipulate the proteins they produce. When glial cells are added to the motor neurons, the glial cells produce myelin, mimicking the processes that occurs during development. Using a combination of electrical measurements and techniques that label specific proteins with fluorescent tags, she will determine the minimum requirements for spinal motor neurons to function correctly. She hopes to discover precisely which glial cells are best able to restore function and also which proteins are most important to the neurons. These cultures also will enable Dr. Xu to test the usefulness of many potential therapeutic agents to improve the ability of these important neurons to conduct signals.
|