New Jersey Commission on Spinal Cord Research (NJCSCR) This data was compiled in compliance with the New Jersey Commission on Spinal Cord Research's statutory mandate, N.J.S.A. 52:9E-1, “…to compile a directory of spinal cord research being conducted in the State.” The information contained within this directory is not all-inclusive. The research projects and researchers listed in this directory are all based in the State of New Jersey, and have applied to and received funding during the fiscal year 2003 grant cycle. The research projects are not categorized, or listed in any particular order. This directory is not a complete listing of all scientific research being performed within the State of New Jersey due to the proprietary nature of the research being conducted at various institutions throughout the State. In addition, institutions are not obligated to share their research information with the New Jersey Commission on Spinal Cord Research. Please feel free to contact the New Jersey Commission on Spinal Cord Research at PO Box 360, Health & Agriculture Building, Market and Warren Streets, Trenton, New Jersey, 08625. The Commission's office can be reached by telephone at 609-292-4055, by fax at 609-943-4213, or by e-mail at For information on the New Jersey Commission on Spinal Cord Research's grant award process, grant applications, and deadlines, please see: www.state.nj.us/health/spinalcord/ 2003 MEMBERSHIP INFORMATION Susan P. Howley, Chairperson COMMISSION PERSONNEL Robert Recine NEW JERSEY COMMISSION ON SPINAL CORD RESEARCH 2003 GRANT AWARD RECIPIENTS PRINCIPAL INVESTIGATOR - MONICA DRISCOLL, PH.D. Project Title Genes that block necrotic cell death will be identified using genetic approaches unique to C. elegans. The devastating consequences of spinal cord injury are largely attributed to death of neurons directly destroyed by the crush and subsequent death of neighboring neurons subjected to the release of toxic molecules from damaged neurons. This secondary necrosis (injury-induced cell death) is a critical intervention target, since necrosis is a major contributor to neuronal loss in injury and since studies suggest that allowing 10 percent of neurons to survive could maintain significant functional capabilities. The goal is to identify molecules that are critical for necrosis by exploiting features unique to the facile experimental organism, the nematode Caenorhabditis elegans. Some key advantages of this system include a transparent body that permits direct observation of dying neurons and scoring for cell survival by observing the living animal under a microscope, and the ability to conduct exhaustive hunts for mutations that block cell death. Wepropose that genetic and molecular dissection of necrosis in C. elegans will identify key molecules needed for the progression through necrosis and instruct us on how to look for related processes in human necrosis. In spinal cord injury and in injury induced by oxygen deprivation (ischemia), neuronal ion channels open more than normal (hyper-activation), which ultimately increases levels of intracellular calcium and causes necrotic cell death. Neuronal damage contributed by sodium channels is clearly important in spinal cord injury. We have developed a C. elegans model in which a mutant sodium channel is hyper-activated to induce necrosis dependent on elevation of intracellular calcium. Our initial work supports that necrotic death mechanisms are conserved from nematodes to humans. Overall, we expect to identify currently unknown conserved molecules that contribute in significant ways to the necrosis that accompanies neuronal injury induced by ion channel hyper-activation. Information generated will allow intelligent design of much needed novel and effective therapies that significantly limit the extent of neuronal death that accompanies physical injury. Results derived from this project may shed light on the molecular mechanisms of necrosis, which is a prominent feature of neuronal degeneration after a spinal cord injury. This grant will bring new information to spinal cord injury researchers. Contact Information: Monica Driscoll, Ph.D. PRINCIPAL INVESTIGATOR - DAVID I. SHREIBER, PH.D. Project Title We will determine optimum gradients of mechanical stiffness and cell adhesion to direct nerve growth. This research addresses fundamental issues in enhancing axon regeneration following spinal cord trauma. The broad long-range objective of this research is to develop biomaterials that provide the most efficient supporting scaffold for axon regeneration and neural tissue engineering. It is hoped this research will allow us to design implantable biomaterials with optimal properties for spinal cord regeneration. We hope to achieve this by systematically investigating the effects of gradients of mechanical stiffness and of cell adhesion sites in vitro to determine the best configuration(s). The tissue environment following spinal cord trauma is not permissive for axon growth, and remains one of the largest barriers to spinal cord regeneration. For the most effective spinal cord regeneration, we must create an environment that not only supports axonal growth, but also directs it. In this way, axons can be enticed to take the shortest path to reconnect with target neurons. The base material is type 1 collagen, which is a common biomaterial used in tissue engineering, and is approved for clinical use in tissue engineering products. Thus, following this optimization, we can begin testing biomaterials with these properties in vivo with many of the concerns of biocompatibility already addressed. While many other factors limit the regenerative capability of the spinal cord, such as fibrosis and astrocytosis, we believe that an optimal biomaterial for implantation will provide a major first step upon which other cues can be incorporated. Biomedical engineering represents the interface between engineering and medicine. We believe this research will yield a defined set of parameters to design biomaterials and will allow us to proceed to in vivo testing with the custom collagen scaffolds, and to also expand the number of parameters to be optimized. The development of biocompatible materials that can be used for spinal cord injury is an emerging discipline with great potential. Contact Information: PRINCIPAL INVESTIGATOR - SALLY MEINERS, PH.D. Project Title The goal is to test whether matrices derivatized with bioactive peptides can promote spinal cord repair. The goal of this proposal is to attempt to repair spinal cord injuries by implanting into the lesion oriented nanofibers whose surfaces are derivatized with bioactive peptides. These peptides, derived from sequences within the neuroregulatory molecule tenascin-C, have been demonstrated in vitro to increase axonal growth and regeneration. We have identified distinct peptides that either increase neurite growth in culture or provide directional cues to growing neurites, a function defined as neurite guidance. These peptides can overcome inhibition to neuronal growth caused by normally repulsive chondroitin sulfate proteoglycans, the major type of inhibitory molecule in the glial scar. This observation is highly significant because full recovery of function following CNS injury cannot occur unless axons elongate and are guided across the inhibitory terrain of the glial scar. Our goal is to evaluate whether the peptides can similarly overcome CSPG inhibition to axonal regeneration in an animal model. The peptides will first be chemically coupled to the surface of nanofibers that have been prepared by electrospinning a polymer solution of polycaprolactone. The resulting fibers have been demonstrated to be biocompatible and permit normal cell growth. The use of these modified fibers will thus provide us with the opportunity to sequester the neuroactive molecules within specific regions of the damaged spinal cord and in this manner provide 1) a scaffold for neuron attachment, and 2) a guide for neurite outgrowth, and 3) an attachment site for the peptides that will prevent their diffusion from the site of injury. This will be the first use of nanofiber technology for the development of peptide-modified matrices for use in therapies designed to treat spinal cord injury. Contact Information: PRINCIPAL INVESTIGATOR - DONGMING SUN, M.D., PH.D. Project Title This project will develop mouse ischemia and contusion spinal cord injury models. Many transgenic strains of mice are available to study the roles of specific genes in injury, repair, and regeneration. Although several mouse models have been described, none have achieved widespread acceptance by many laboratories. At the W.M. Keck Center, we developed, validated, and maintain the widely used Impactor model of rat spinal cord contusion. We have experience designing models and outcome measures that are consistently applied by many laboratories. We propose to test and validate two mouse spinal cord injury models that mimic two commonly encountered types of human spinal cord injuries, i.e., graded ischemia due to compression and graded contusion of toracic (T13) spinal cord. We will compress the spinal cord for 10, 20, or 30 minutes or contuse the spinal cord by dropping a 10-gram weight 6.25, 12.5, or 25.0 mm. The models will be assessed in C57B1/6 strains of mice. In the first year the mice will be assessed for tissue damage and gene expression at 1, 3, 6, 12, and 24 hours after injury. In the second year, we will examine the mice for neurophysiological, locomotor, and histological changes at 1 day, 2 weeks, and 6 weeks after injury. All the data will be placed on a database that will be available to other spinal cord injury researchers. It is hoped that these experiments will provide the baseline mouse spinal cord injury data for other laboratories who adopt these mouse models. The database will serve as a repository of information for all researchers who utilize these models. The establishment of standardized mouse model will greatly accelerate research in the field and allow researchers to compare their data. It should significantly reduce duplication and provide a platform for a network of researchers to collaborate with each other. Contact Information: PRINCIPAL INVESTIGATOR - BONNIE LYNNE FIRESTEIN, PH.D. Project Title The proposal will test ways to decrease neuronal death by decreasing neurotoxic signaling molecules. This proposal focuses on a way to protect neurons from dying during spinal cord injury. The work will address a way to block one of the most destructive pathways that occur when there is an insult to the spinal cord. During spinal cord injury, a neurotransmitter called glutamate is released in extremely high quantities. This glutamate can then act on proteins called receptors that transduce signals into the neurons. These signals include chemicals called reactive oxygen species or ROS that have detrimental effects on the neurons, and these effects often lead to neuronal death. Until now, very little is known about how we can block either the receptors that lead to the production of the ROS or how we can block or bind up the ROS so that they cannot do damage to the neurons. This grant will focus on identifying methods to block either one or both of these steps. First, experiments will be performed to try to bind up the ROS. Spinal cord cultures will be treated with a chemical called uric acid. Uric acid has been shown to slow down the progression of disease in an animal model of multiple sclerosis and to bind to ROS. The cultures will also be treated with excess glutamate. The amount of neuronal death in the presence and absence of uric acid will then be compared. It is expected that treatment with uric acid will decrease neuronal death. Cypin protein is a protein that leads to increased uric acid production. In parallel with uric acid treatment, we will try to increase the amount of cypin protein in the spinal cord neurons to see if this treatment will also protect the neurons from glutamate-mediated toxicity. Cypin protein also decreases glutamate receptor and signaling proteins at the synapse, or signaling site of a neuron. Testing will be performed to see if increasing cypin decreased glutamate receptor signaling, and hence decrease ROS. By decreasing signaling, neuronal death should decrease. The combination of cypin's role in binding ROS and decreasing receptor signaling can lead to promising therapies that will decrease neuronal death during spinal cord injury, maintaining normal spinal cord function. Contact Information: PRINCIPAL INVESTIGATOR - RONALD P. HART, PH.D. Project Title This proposal will identify genes associated with regeneration of nerves from the brain into injured spinal cord. The ultimate goal of spinal cord injury research is to restore function, most likely through regeneration. Recent results from other laboratories have identified several new regeneration schemes. In general, local inhibition of regenerating axons by the environment of the injured spinal cord must be reversed. After this reversal of inhibition, brain neurons are coaxed into regenerating through the injured spinal cord, and others have shown that this is still possible at least one year after injury. We believe that changes in the activities of specific genes are required for neurons to regenerate. We previously adapted a new molecular biology technique ("gene chips") for use in rat spinal cord injury. We now propose to use our tool to identify regeneration-associated genes. First, we will compare two common models of spinal injury, contusion and axotomy. Then we will use two of the recently developed regeneration strategies to encourage regeneration from the brain through the injured spinal cord, comparing gene expression with injury alone. The cells we will examine are specific for motor function, including walking. By identifying "regeneration-associated genes" we hope to 1) identify specific cellular pathways that are required for regeneration, and 2) provide other researchers with measurements useful in judging regeneration activity, and 3) provide new targets for regeneration drug development. This project will not only support our studies of the genes required for regeneration, but also help to establish New Jersey as a center for genomics studies of spinal cord injury. Contact Information: PRINCIPAL INVESTIGATOR - WISE YOUNG, PH.D., M.D. Project Title Replication of the Kawaguchi neonate study in an adult model of injury. In 1994, Dr. Saburo Kawaguchi reported extensive regeneration of sharply transected and anastomosed spinal cords of neonatal rats. This method could not be readily applied to adult rat spinal cords because the cut ends retract after transected, leaving a physical gap that regenerating axons cannot cross. To solve this problem, Dr. Tsutomo Iseda worked with Kawaguchi to develop a method of removing a vertebral segment to allow close apposition of transected rat adult spinal cords. They also found that placing embryonic astrocytes at the connection interface significantly reduced aberrant axonal growth. Using this approach, they achieved remarkably complete and functional regeneration of transected adult rat spinal cords. No other laboratory has accomplished such spinal cord regeneration in adult rats before. Dr. Iseda will come to the W.M. Keck Center for Collaborative Neuroscience to repair and regenerate chronic contused rat spinal cords. This is an excellent collaborative opportunity between two leading spinal cord injury laboratories. The Kawaguchi laboratory has more experience with reconnecting transected spinal cords and tracing regenerated spinal cord tracts than any other laboratory. Our group developed the Impactor model of rat spinal cord injury, and helped develop the BBB scale, a widely used behavioral score of locomotor recovery. The model mimics human spinal cord injuries from blunt contusions that produce wide areas of tissue destruction. In addition, we have experience culturing and transplanting olfactory ensheathing glial, radial cells, and stem cells obtained from a transgenic rat that expresses green fluorescent protein (GFP), allowing unambiguous identification of transplanted cells. We have the capability to assess gene expression of regenerating systems. This confluence of expertise, experience, and desire to collaborate is unique and timely. Contact Information: PRINCIPAL INVESTIGATOR - GAIL FORREST, PH.D. Project Title To evaluate independent walking after incomplete SCI through body weight support treadmill training. This proposal addresses two major problems of spinal cord injury subjects, mobility and cardiovascular autonomic function. This proposal will evaluate independent walking after incomplete spinal cord injury through body weight support treadmill training. Although the primary purpose of rehabilitation is to regain walking, many individuals with spinal cord injury do not regain the ability to walk. Any walking improvements are limited by insufficient muscle activity to promote stepping, maintain balance and cope with weight bearing problems. Typically, traditional rehabilitation includes stretching, strengthening and functional gait with assistive devices; however, gait performance plateaus and is followed by minimal improvements. Recently researchers have suggested and demonstrated that a preferred alternative to traditional rehabilitation is treadmill training where the body is supported by an overhead harness attached to the trunk. Treadmill training with body weight support has the potential to restore walking independence. The suggestion is that the spinal cord can perform on its own without input from the brain. Research suggests that the spinal cord neuronal circuits may "learn" or be retrained by rhythmic loading and unloading of limbs during locomotion with body weight support while walking on a treadmill. The ultimate goal is to allow the individual to walk overground with increased walking velocity and coordination. The main aim of this study is to investigate the effectiveness of progressive treadmill training with body weight support while treadmill walking for incomplete spinal cord injury compared to a traditional training rehabilitation intervention. The Principal Investigator will also investigate how training can lead to independent overground walking. This study may validate previous research findings regarding the efficacy of the training method. Replication of these studies is immensely important. Contact Information: PRINCIPAL INVESTIGATOR - MARTIN GRUMET, PH.D. Project Title To analyze why cells die following injury and to find ways to improve survival of transplanted cells. This proposal will analyze why cells die following injury, and find ways to improve survival of transplanted cells. This proposal addresses one of the most important elements responsible for the progressive destruction of spinal cord tissue following an initial injury, the local production or accumulation of cytotoxic factors in the damaged cord. Following traumatic spinal cord injury, there is a short period in which neurons (nerve cells) die and a much longer period during which glial cells (the major cells in the brain that are not nerve cells) die. Understanding what causes these cells to die is of great importance for the design and testing of new therapies to improve recovery following injury to the central nervous system. However, little is known about molecular mechanisms that underlie the death of cells in the spinal cord following injury. Therefore, there is a need for in vitro models to study molecules responsible for cell death. By the utilization of a test to measure cell killing activity that is present in extracts of contused, but not normal spinal cord, the intent is to analyze the nature of the cell killing activity. Testing will determine quantitatively how much activity is generated and how long it persists following traumatic spinal cord injury. A glioma cell line will be used to pilot the test as well as neurons, and glia (astrocytes and oligodendrocytes). The sensitivity of neural stem cells (which can give rise to nerve cells) will be evaluated for transplantation to promote nerve regeneration. Parallel studies will be performed to analyze the survival of stem cells transplanted into the spinal cord at various times following contusive injury. The second aim of this proposal is to determine the biochemical nature of cytotoxic activity. Treatments that disrupt proteins, as well as gene chip analysis, will be performed to identify groups of genes that correlate with acute and extended periods of death of neurons and glia, respectively. This combined approach will focus on those molecules that play critical roles in cytotoxicity. Contact Information: |
