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Research Abstracts

The first recorded incident of spinal cord injury (SCI) was of a man hurt while building one of the great pyramids. SCI, considered untreatable, has plagued humans for centuries, however recent research has brought great hope. During the past 15 years, research has shown us that treatments for SCI may indeed be possible, although answers to fundamental problems are still needed. The Roman Reed Spinal Cord Injury Research Fund of California is providing support to move SCI research toward human treatments faster.

The projects supported in 2004-2005 cover a board range of research areas, including understanding pain following SCI, recovery of hand function in a primate model, and inhibitory molecules and regeneration. Of 42 applications, the 14 projects summarized below were chosen as Roman Reed Research Projects. The projects have been grouped into rough categories, although several belong in multiple areas.

Neural Protection

The human body does you no favors in its response to central nervous system (CNS) injury, and indeed, causes significant additional damage. The initial traumatic or mechanical insult to the spinal tissue is only the beginning. Within hours to days of injury, a cascade of immunological and other events takes place that can cause the enlargement of the injury site by several segments, resulting in additional loss of function. Seeking to prevent this secondary damage and protect the nervous system from additional damage immediately after SCI is a key area of research.

Is 17--Estradiol Protective After Spinal Cord Injury in Rats?
Candice Floyd, Ph.D.
University of California, Davis

Men with spinal cord injury out number women 4 to 1 (80-85% to 15-20%), and while some of this gender difference may be related to life-style, other factors may be involved. Human research on other types of CNS injury, like stroke, suggests that women show less damage following injury than men. This has led to the theory that estrogen is neuroprotective. There is encouraging evidence from research in stroke, Alzheimer's and Parkinson's disease, and traumatic brain injury that estrogen is beneficial, although these studies have shown that not all estrogens are equally effective. Indeed, recent reports from a large clinical trial suggest that the type of estrogen, as well as the route of administration, may be critically important. 17--estradiol is an estrogen that has already been approved by the FDA for use in humans, and is of the type thought to be effective. Dr. Floyd is exploring the possible protective properties of this estrogen by examining its effect on walking and bladder functioning following SCI. This is a treatment that would be given within hours of injury to block secondary degeneration. If this estrogen is found to be neuroprotective following spinal cord injury in rats, Dr. Floyd's studies will lay the essential ground work for a potential acute SCI treatment with an already FDA approved therapy.

Inhibition and Regeneration

In humans, during development, there is massive neuronal growth. Once functional connections are made, this growth is shut off by a variety of inhibitory mechanisms that prevent the nervous system from growing out of control. The problem is, after a spinal cord injury, these inhibitors stop nerve cells from regrowing. The stop signs that are so important in normal development become a major roadblock to regeneration. Over the past decade or so, several of these stop signs have been identified and research programs have been set up to find ways to remove them, go around them, and otherwise change the cellular environment to allow for regeneration. Several Roman Reed projects address inhibitory mechanisms and look to improve endogenous regeneration.

Functional Analysis of Nogo in CNS Axon Regeneration Using a Nogo Null Mutant
Binhai Zheng, Ph.D.
University of California, San Diego

Scientists have long recognized that the environment of the CNS, the brain and spinal cord, is inhibitory for regeneration, and that Nogo, a small protein made by myelin (the insulation that wraps around axons and allows neurons to send electrical signals) is a part of the inhibition story. One way to look at the role of Nogo is to examine animal models that do not have Nogo. We do not know of existing animals that lack Nogo, but we can make them through a process called transgenics. We know a great deal about the mouse genome and can manipulate it to add specific genes, knock-in models, or remove specific genes, knock-out models. Several research groups have generated different mouse models that change the Nogo gene, and interestingly, the different models show mixed results, with some showing no regeneration, some showing a little regeneration, and some showing robust regeneration. Recently, it has become clear that none of these models completely disrupt or knock-out the Nogo gene.

Dr. Zheng has developed a transgenic model that completely eliminates Nogo. This model may allow him to fully characterize the role of Nogo in blocking regeneration. If his mice show good regeneration, this would provide strong evidence that regeneration can be enhanced with the removal of Nogo from the cellular environment. Alternative, if the regeneration Dr. Zheng sees is minimal, this would suggest that other inhibitory molecules in the spinal cord need to be examined in greater detail. Either way, Dr. Zheng's work may finally clarify the Nogo story, and provide critical insights into therapeutic approaches for overcoming the inhibitory environment of the newly and chronically injured spinal cord.

Structure of Proteins That Inhibit CNS Repair: Nogo and It's Receptor
Melanie Cocco, Ph.D.
University of California, Irvine

The best known of the major inhibitory molecules is a small protein called Nogo. Its name suggests it's function, this protein stops axons from regrowing after injury. The Nogo protein is like a key that fits into a lock, called a receptor, which is located on an axon. Turning the receptor lock with the Nogo key stops regeneration. Preventing Nogo's action potentially can be accomplished in 2 different ways; (1) by changing the shape of the Nogo protein so that it no longer fits in the receptor, or (2) by changing or jamming the lock. In either case, we need to know what Nogo is made of and what it looks like.

Dr. Cocco is tackling this problem using a novel technique, nuclear magnetic resonance (NMR) spectroscopy. Typically, the shape and composition of a protein is discovered by using x-ray crystallography; a process whereby the protein is crystallized, an x ray beam is shown through it, and the changes in the beam's direction, or scatter, are measured. The changes allow scientists to determine the molecular structure of the protein. The problem is Nogo does not crystallize. NMR, on the other hand, does not require crystallization as this techniques is quite similar to magnetic resonance imaging (MRI). In much the way doctors are able to look into your body with an MRI, NMR spectroscopy may allow Dr. Cocco to look into the Nogo protein and determine what it is made of and what it looks like. Knowledge of Nogo's structure should enable Dr. Cocco and her colleagues to design a molecule that changes the Nogo key or receptor lock and blocks Nogo's action. The NMR spectroscopy technique will also be used to aid in the development of therapeutic agents designed specifically to block Nogo as part of an SCI treatment to promote neural repair.

Genetic Manipulation of Scar Forming Astrocytes, and Biopolymer Tissue Support for Acute and Chronic Spinal Cord Injury
Michael Sofroniew, M.D., Ph.D. and Ben Wu, Ph.D.
University of California, Los Angeles

Astrocytes, a type of cell found in the spinal cord, have many different forms and functions. After SCI, reactive astrocytes form a physical barrier around the injury site that walls off the area from the rest of the spinal cord. This effectively restores the blood brain barrier, a plus, but also creates a scar that prevents regeneration of neurons. Dr. Sofroniew and his colleagues have been studying the astrocyte scar, and using a transgenic model, were able to create a mouse that does not form an astrocyte scar after injury. This mouse shows modest, but significant increases in axon regrowth after SCI. However, there is also increased tissue disruption and death of nerve cells around the injury, as well as loss of motor function. This clearly shows that astrocytes play both positive and negative roles following SCI. Dr. Sofroniew is now working on discovering how the astrocytes do different jobs, scar formation vs. maintaining neural heath, with a new transgenic mouse model created by his group.

In a parallel line of research, Drs. Sofroniew and Wu are looking for ways to support the regeneration seen when there is no scar. They have created tiny time-release capsules, microspheres, filled with a molecule, laminin, that regrowing axons like. They are also helping the regenerating axons by providing guide wires across the injury site in the form of microfibers. Both of these structures are created with biopolymers, naturally occurring molecules like carbon are used to build tiny structures. The biopolymers the Sofroniew group is using are already approved in humans for drug delivery outside of the CNS, so approval for use in the CNS in humans should be rapid. The last phase of these experiments involves combining the transgenic model with the microspheres and microfibers to hopefully get extensive and useful regeneration across the injury site. They plan to test this in both acute and chronic injury models.

The Contribution of Protein Kinase C to Corticospinal Tract Regeneration
Allan Basbaum, Ph.D. and Simona Neumann, Ph.D.

University of California, San Francisco

There are several board categories of inhibitors or stop signs that prevent regeneration after SCI. The astrocyte scar is one. Another is injured axons do not seem to grow as well as uninjured ones. The environment is a third. It seems there are fewer growth supporting molecules in the cellular environment after injury. Also, molecules that specifically inhibit or stop regeneration suddenly show up. Drs. Basbaum and Neumann suggest that some nerve fibers actually give off one of these molecular stop signs. The fibers in question are in the corticospinal tract, which is a bundle of nerves running from the brain through the spinal cord that, in humans, carries information for most types of movement. The molecule in question, protein kinase C isoform, is found at a place on the nerve fiber that suggests it plays a role in the growth of the fiber. That is, protein kinase C isoform seems to be a regulator of nerve fiber growth for the corticospinal tract. Evidence for this comes from development. This molecule is not found during development, likely because growth of the nerve fibers at that time is essential. After development, the molecule is thought to be produced so as to stabilize the neural connections. The emergence of this molecule after development and correlating with restricted corticospinal tract growth, supports the idea that protein kinase C isoform is an inhibitor of regeneration after injury.

Unfortunately, in the event that injury occurs, the presence of protein kinase C isoform provides a critical hurdle that must be overcome if regeneration is to occur. Dr. Basbaum is assessing the function of protein kinase C isoform during nerve cell regeneration. He and his group are using a transgenic mouse model to test whether elimination of this molecule in adult animals improves the regeneration of injured corticospinal tract nerve fibers. They are performing studies in normal mice and in mice in which the gene that encodes protein kinase C isoform is removed. This work may lead to the development of new approaches to enhance functional recovery after spinal cord injury.

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Improving Motor Recovery

The past decade has shed light on the ability of the spinal cord to direct, under certain circumstances, walking independent of the brain. With step training and body weight support, rats and humans with SCI are able to relearn to walk. The processes underlying this ability are generally understood, but we still have much to learn about the mechanics of motor function, both walking and hand/finger function. Several Roman Reed research projects are dedicated to better understanding spinal control of motor systems and how motor pathways are modified after injury with an immediate goal of improving function.

Neural Mechanisms Underlying Locomotor Behavior Induced by Epidural Electrical Stimulation
V. Reggie Edgerton, Ph.D. and Ronaldo Ichiyama, Ph.D.
University of California, Los Angeles

Dr. Edgerton and his group, in work funded by the Roman Reed program, have developed a technique to improve recovery of walking on a treadmill with body weight support in a rat model. Following complete transection of the spinal cord, a tiny wire called an electrode is implanted on the surface of the spinal cord at L2, which controls the hips and contains large numbers of motor neurons (the lower motor neuron pool). Short busts of electrical current, called epidural stimulation, are passed through the wire into the spinal cord, which stimulates the leg muscles. In addition to electrical stimulation, quipazine, a drug that increases the amount of the neurotransmitter serotonin, is given. Together, stimulation and quipazine produce rhythmic, alternating stepping on the treadmill, with some animals showing coordinated steps with proper foot placement and a clear and appropriate stepping pattern.

Indeed, epidural stimulation in combination with quipazine produces the best stepping of any treatment this group has previously tested. However, more information is needed about the specific mechanisms underlying this potential therapy. To that end, Drs. Edgerton, Ichiyama and their colleagues are examining a host of issues, the role of sensory information from the foot and ankle in the coordination of locomotion; the progressive changes in spinal reflexes as a result of a spinal transection and daily epidural stimulation; the cellular environment and the connections between neurons; and the fatigue, both neural and muscular, that may result from continuous epidural stimulation, to refine this technology for human application.

Biochemical mechanisms involved in spinal learning
Niranjala Tillakaratne, Ph.D.

University of California, Los Angeles

The conventional belief thus far has been that learning and memory takes place in the brain, specifically in the hippocampus and cortex. As it turns out, there is now very good evidence that the spinal cord can learn and remember as well. Rats with complete spinal transections, a situation where the brain cannot talk to the spinal cord below the injury, are able to learn and remember motor tasks. Step training (body-weight supported on a treadmill) is an excellent example of this. Over training sessions, stepping ability improves, indicating that the spinal cord has the ability to learn tasks independent of the brain. When the brain learns and remembers certain parts, particularly the hippocampus, show changes in the cells and the cellular environment. These changes trigger a cascade of events that result in a change in the levels of several proteins. Dr. Tillakaratne is asking whether the mechanisms involved in the spinal cord learning to step are the same mechanisms we see with learning in the brain. She has already found that levels of two of the proteins that increase after learning and memory in the hippocampus are also changed in the spinal cord. She is now looking at other key proteins found in the brain, as well as using drugs that block the changes in proteins to see if she can disrupt spinal step learning and memory. Understanding the mechanism by which we learn to step is important information that may allow us to (1) pharmacologically target specific pathways in the nervous system and (2) improve the efficiency of stepping in spinal cord injured patients.

Inducible long-term facilitation of motoneuronal discharge as a mechanism for recovery of motor function: the dependence on PKC activity
Jack Feldman, Ph.D.
University of California, Los Angeles

Motoneurons transform the internal actions of the brain into behavior, translating patterns of neuron-to-neuron activity into commands for muscle contraction and relaxation. How motoneurons respond to input from other neurons and muscles, and how their responses are regulated is of considerable interest and is basic to understanding neural control of movement. Dr. Feldman and his colleagues are particularly interested in understanding the neural control of spinal stepping, however he is using a breathing model to explore this. Breathing is a fundamental process produced by movements generated and controlled by the CNS. The study of respiratory movements has certain distinct advantages; the movements are comparatively simple and are well understood. Moreover, breathing movements can be studied in a reduced preparation. Here a slice of spinal cord living in Petri dish is the model. Obviously, a slice of tissue is much less complicated than the whole animal and because of this, we can ask questions of this model that we simply could not explore otherwise.

Dr. Feldman has reported that motoneurons that control both breathing and stepping show similar changes following repetitive activity. Motoneurons involved in stepping change the way they communicate with other neurons after step training, specifically they become more excitable. The motoneurons involved with breathing show the same changes after a breathing task where the tissue is deprived of oxygen for several minutes at repeated intervals. The neurons in this situation become more excitable and breathing behavior improves. This process, be it changes after step training or a breathing task, is called plasticity. Our nervous system is able to change and adapt with experience, which lets us learn and remember. Dr. Feldman is examining what happens inside and outside of the motoneurons after training induced plasticity. Ultimately, he believes that understanding the neuron-to-neuron interactions that underlie motoneuronal plasticity will aid in developing therapeutic strategies for functional recovery from spinal injury. In particular, this work may lead to drug interventions in concert with rehabilitative training paradigms to regain muscle function.

Hand function and the involvement of descending motor pathways following a cervical dorsal root lesion in monkeys
Corinna Darian-Smith
Stanford University School of Medicine

Control of movements involves information from the brain being sent down the spinal cord, through the ventral roots and out to the body, as well as sensory information being sent from the body through the dorsal roots into the spinal cord and up to the brain. Motor commands from the brain and sensory feedback from the body are integrated to create coordinated movements. Cervical dorsal roots consist of sensory nerve cell fibers that supply the arm and hand. Damage of these dorsal roots in humans is often seen from birth injuries or impact trauma in adults, and typically causes a severe and permanent loss of manual dexterity, the ability to manipulate objects with the hand. More limited dorsal root lesions impair fine manipulative movements that depend on sensory feedback from the fingers, like the ability to reach into your pocket and pullout a dime rather than a nickel. To mimic this injury, Dr. Darian-Smith and her colleagues have developed a primate model where a part of the dorsal roots, dorsal rootlets, that transmit touch information from the thumb and index finger to the brain are selectively cut. This model allows Dr. Darian-Smith to study how the nervous system normally responds to injury, and more importantly, how we might best optimize recovery of function.

The dorsal rootlets control the ‘precision grip' achieved by opposing the thumb and index finger. When the dorsal rootlets are cut, precision grip is lost and there is no activity in the brain region that normally receives sensory information from the thumb and index finger. In the months following injury, there is a significant, albeit partial, recovery of precision grip, and a return of activity to the corresponding region of the brain. However, Dr. Darian-Smith has found that the nerve cells of the dorsal rootlets that are cut by the lesion do not regenerate. This recovery of function is due to the intact nerve cells in dorsal rootlets that border the lesion. These rootlets are too few in number and /or limited in their connections at the time of the injury to have any significant effect on the impaired hand function, but in the weeks following injury these intact central nerve fibers sprout to form new connections.

But is this the whole story? Emerging evidence suggests that even though the spinal cord is not damaged following lesions of the dorsal rootlets, there is cell death and reorganization in the cord weeks to months after injury. It may be that this reorganization in the spinal cord is responsible for the return of ‘precision grip' hand function. Determining how hand function recovers after dorsal root lesion is critical for developing appropriate treatment strategies to optimize functional outcome in humans.

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Autonomic Function

Paralysis is the most obvious result of SCI, however according to a recent survey, people with SCI reported that return of bowel / bladder and sexual function would most improve quality of life. These are autonomic functions, functions over which we have little conscious control. A major autonomic dysfunction after spinal cord injury involves the development of pain. For largely unknown reasons, some people develop debilitating pain below the level of their injury even though they may have no ability to feel touch, hot or cold, or a pin prick. Current drugs for SCI pain management often provide incomplete relief, and the use of these medications is often limited by undesirable side effects. Clearly, there is an urgent need for better management of SCI pain.

Plasticity in Pain Behavior and in Nociceptive Projections to the Lumbosacral Spinal Cord in a Rat Cauda Equina Injury and Repair Model
Leif Havton, M.D., Ph.D. and Allison Bigbee, Ph.D.
University of California, Los Angeles

Approximately 20% of all SCI are to the cauda equina/conus medullaris (CE/CM), or horse's tail, region, which is the very end of the spinal cord. With this injury comes loss of motor, bladder, and bowel function, and often, excruciating pain that extends beyond the site of the injury. Drs. Havton and Bigbee are examining CE/CM pain from several angles with the goal of determining why this pain occurs, and what can be done to alleviate the symptoms. First, they want to better understand the development of the pain and so are charting the time course from injury to emergence of the pain response. They are also examining 3 specific molecules involved in pain processing to see how these molecules are changing in and around the lesion site.

Drs. Havton and Bigbee have developed a clinically relevant model of CE/CM SCI in rats, which involves the avulsion, or tearing, of the lumbosacral L6-S1 ventral motor roots from the one side of the lower portion of the spinal cord (i.e., ventral root avulsion, or VRA). These ventral roots are the nerve fibers involved in providing motor function to the pelvic muscles, bladder and bowels. This one sided lesion is fairly mild in that walking is normal in these rats, and some bladder function is maintained. However, touching the bottom of either hind paw with a blunt probe, like the eraser end of a pencil, elicits a pain response that does not occur in uninjured rats. The paw on the same side as the SCI is also hypersensitive to heat. In addition to using this model to explore the underlying mechanisms of the pain response, they are also exploring the use of a therapeutic reimplantation strategy to place these ventral roots back into the spinal cord. Drs. Havton and Bigbee have already shown that reimplantation in rats improves axonal regeneration, but now they are determining whether this procedure also reduces pain. These important experiments may translate directly into therapeutic strategies for SCI patients, as the reimplantation strategy potentially could be performed in humans today.

Identifying new targets and pathways for management of spinal cord injury pain
David Luo
University of California, Irvine

Dr. Luo is studying pain by examining genes and their products, proteins, in the cord. Genes are much like the instruments in a symphony orchestra, each plays its own part, but together they make music. Pain is thought to be caused by the action of specific genes working together, and the spinal cord is an important place for the processing of pain information. Why pain develops after SCI is still a mystery, however after SCI many of the genes in the spinal cord change their activity, and likely, the way they work with other genes. Dr. Luo believes that changes in the specific spinal cord genes, and thus in the music played by the genes, may contribute to the development of chronic pain. His project involves determining which genes change after injury and, of those, which are responsible for pain. To do this, he is using cutting edge technology. With gene chip microarray techniques, he is able to look at thousands of genes and their interactions simultaneously. However, how do you tease out the ones that change due to injury and the ones specific for pain? To do this, he is using a rat SCI model where about 50% of the animals spontaneously develop pain in the weeks following injury. Since all the animals have the same injury, injury-induced changes to genes should be the same across all animals. However, the ones that develop pain should have additional genes that have changed. Dr. Luo is comparing the gene profiles before and after the onset of SCI pain, and between SCI rats with or without pain. Once we have information on the genes involved in pain development in hand, development of new therapeutic agents or strategies for better pain management in SCI patients may follow rapidly.

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Models and Techniques

In order to find treatments for spinal cord injury, researchers need good tools. These tools allow us to ask questions like did the treatment result in better functional recovery, is a specific molecule responsible for blocking regeneration, and which cells survived after transplantation. Tools include the correct animal models. Rats and mice are excellent animal models for spinal cord injury research. Rats have much the same physical response to injury that humans do, and we know a great deal about mouse genetics and so are able to manipulate their genes to ask all manor of questions. Of course there are major differences between rodents and humans, not the least of which is size, so models using animals closer in size and structure to humans will be needed before going to clinical trial with some therapies. In addition to models, research tools also include techniques that allow us to ask new questions, examine problems in a new way, or get information that was previously inaccessible. Development of such tools is an essential part of spinal cord injury research and will play a critical roll in all treatments.

University of California Consortium to Study Axonal Plasticity and Regeneration in the Primate Spinal Cord
Mark Tuszynski, M.D., Ph.D.
University of California, San Diego

Rodents, usually rats and mice, are the front line research subjects for the study of SCI repair. For many good reasons, rodent SCI models allow researchers to explore therapeutic avenues rapidly. Over the past decade, these models have brought to light several potential therapies, from stem cells to gene delivery of growth factors to neuronal plasticity and recovery of function. However, humans are primates, and there are distinct differences between rodent and primate spinal cord systems, including: 1) Size. Regeneration of an injured axon in the rat over several millimeters might be sufficient to generate functional recovery, whereas distances of many centimeters might be required in the primate spinal cord. 2) Anatomy. There are important differences in the organization of the rodent and primate spinal cord. Both have bundles of axons, called tracts, that travel from the brain through the spinal cord and carry specific types of information, however, there are differences in the number of axons and the location of tracts within the cord in primates as compared to rodents. 3) Function. Some important tracts have different functional roles in primates and rodents. For example, the corticospinal tract is critical for most movement in humans, but not in rats. On the other hand, the rubrospinal tract is important for forelimb movement in rats, but is functionless in humans.

The California primate consortium is well on the way to establishing a primate model of SCI. The injury itself is mild, but the functional losses are clear and measurable. In additional to developing the model, which ultimately many therapies on the way to clinical trial will likely use, Dr. Tuszynski and the consortium are testing a potential therapy, gene delivery growth factor, and examining neuronal plasticity and functional recovery. Thus, the work of this consortium is focused both on enhancing our mechanistic understanding of injury to the primate spinal cord, and on developing practical and validated therapies that could undergo human testing in the future.

Novel Microfluidic Technologies for Sorting and Differentiating Neural Stem Cells
Edwin Monuki, M.D., Ph.D.
University of California, Irvine

Almost all mammals, following SCI, develop a fluid filled cavity in and around the injury site. The cavity is formed by the death of CNS tissue as a result of the initial injury and body's response to the injury. One avenue for therapeutic research is based on replacing the lost tissue. Ideal cells for replacement therapies are ones that are able to move around the spinal cord so they can go where they are needed and divide to create more of the same replacement cells as needed. Stem cells fit this profile. They are young cells that can migrate through tissue and can divide easily and rapidly. Dr. Monuki and his colleagues are working with neural stem cells. Unlike embryonic stem cells, these cells are already destine to become only central nervous system (CNS). The problem is there are many cell types in the CNS. For therapies, we would like to be able to select specific cell types to be transplanted, nerve cells or myelin makers (oligodendrocytes), and exclude others, scar forming astrocytes for example.

Dr. Monuki and his colleagues are developing a new technique, microfluidic cell sorting, for determining what different neural stem cells will turn into and better understand what makes them become one type of cell rather than another. It seems that cell types, or subpopulations, have a unique electrical fingerprint. The electrophysiological profile of neurons is different than myelin makers is different than astrocytes. Dr. Monuki and colleagues have been able to sort the neural stem cells based on their electrical fingerprint. Think of a handful of dimes, nickels, and quarters. The microfluidic technique is like putting the handful of coins in a change machine that sorts all the dimes to the right tube and the nickels to the left tube. Coins are sorted to different tubes by their size, with microfluidics, electrical signatures are used for sorting. The sorted cells are then exposed to specific conditions, different growth factors or combinations of growth factors, to encourage the formation of mature CNS cells that would help replace tissue lost after SCI. By achieving a greater degree of control over neural stem cells, Dr. Monuki and his colleagues should be able to improve their ability to contribute to the healing of the damaged spinal cord.

Microfluidic Platform for High Throughput Screening of Agents for Spinal Cord Axonal Regeneration
Noo Li Jeon
University of California, Irvine

What happens to an individual nerve cell after injury? How does a regrowing axon respond to different growth factors or inhibitory molecules? These are difficult questions to find answers for given the exceptional complexity of humans, or even rats. These questions really cannot be answered with typical rat SCI models, called in vivo models. In vivo means you look at the whole animal, and with millions of cells, trying to study just one is beyond needle in the hay stack. Dr. Jeon and his colleagues are answering these questions by simplifying the model. Using an in vitro technique, looking at part rather than the whole, they are looking at individual nerve cells that live in a specially designed multi-chambered device. Single nerve cells are put in one chamber, and their axons grow through tiny grooves in a connector to another chamber. Dr. Jeon can cut or damage the axons and watch them regenerate. Moreover, he can add nerve growth factors or inhibitory molecules, like Nogo, and see how the axons regenerate in those environments. The device is designed to allow for the use of high-powered microscopes to see the neurons and time-lapse photography to film the regeneration of axons. Success with this device will enable rapid screening of various molecules and drugs that may be helpful to axonal regeneration.