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Basic Science Research
The International Center for Spinal Cord Injury (ICSCI) is fortunate to have a dedicated group of basic science researchers investigating the potential means to cure paralysis. The ICSCI basic science team utilizes in vivo (cellular) and in vitro (animal) models to study various aspects of neurological disease, injury, and recovery. Our ongoing areas of research focus include several integrated approaches to investigating targets for therapy.
Many central nervous system (CNS) injuries (such as spinal cord injury) and CNS diseases (such as multiple sclerosis) lead to white matter damage within the spinal cord which renders the CNS dysfunctional. White matter consists mostly of glial cells and myelinated axons which are responsible for transmitting signals from the brain to the spinal cord. Damage to this area of the spinal cord can disrupt sensory and motor signals causing neurological impairment or paralysis.
Myelination controls the pace at which electrical signals travel down the axon and Oligodendrocytes are one of the cells responsible for myelinating axons. By studying how nerve cells (neurons) and oligodendrocytes interact in the central nervous system to produce myelinated axons, we hope to better understand this process and generate new types of therapy that promote CNS function following injury or disease.
Functional Electrical Stimulation and Activity-Based Restorative Therapy
Physical rehabilitation following a spinal cord injury-related paralysis has traditionally focused on teaching compensatory techniques, thus enabling the individual to achieve day-to-day function despite significant neurological deficits. But the concept of an irreparable central nervous system is slowing being replaced with evidence related to the central nervous system’s plasticity and ability to repair and regenerate. In our clinic, functional electrical stimulation (FES) is used as a part of our Activity-Based Restorative Therapy and involves the use of electrical current applied on top of the skin to cause muscle contractions. In our lab, we use animal models and in vitro experiments to investigate the proposed mechanisms that lead to recovery in response to FES including synaptogenesis, myelination and re-myelination, new cell birth, and reorganization and repair with the central nervous system in our efforts to discover the means to treat and cure paralysis.
Induced Pluripotent Stem Cells
Induced pluripotent stem cells or iPSCs are adult cells such as ordinary skin or blood cells which have been genetically reprogrammed to an embryonic stem cell-like state. These iPSCs, when exposed to the right environment have the potential to become almost any cell within the body. Unlike embryonic stem cells, which have similar potential, these iPSCs can be derived from the specific patient that they would be used to treat. Modeling neurological disorders has remained a challenge despite advances in transgenic technologies, the use of iPSCs breaks down many of those challenges and by modeling neurological disorders on a cellular level we can better understand the genetic and epigenetic factors involved in neurological recovery. By using patient-specific central nervous system cells derived from iPSCs, we can first identify the specific epigenetic modifications necessary to promote recovery of function and in turn we could then develop patient-specific molecular therapies for spinal cord injury.
Note: Our current induced pluripotent stem cell (IPSCs) studies focus solely on animal and cell models.
Since the groundbreaking discovery of DNA there’s been the assumption that DNA is what makes us who we are. But when it comes to our genome, it is less about what the genes are but rather when and how they are turned off and on again, and in which combinations. These changes are epigenetics, the study of these heritable changes in gene expression and observable cellular traits.
Our research center is focused on identifying the epigenetic changes affiliated with neurological recovery in chronic spinal cord injury. Because it is believed that injury causes epigenetic changes on the cellular level and that some of these epigenetics modifications may present an additional barrier to recovery, identification of epigenetic changes that are associated with injury and subsequent recovery is essential. Technological advances in DNA sequencing enable genome-wide epigenetic mapping associated with various biological processes. By using these mapping techniques to identify therapeutic targets and to monitor the effectiveness of ABRT (Activity Based Restorative Therapy) for the treatment of SCI, we will be able to determine if ABRT associate recovery involves epigenetic changes. Epigenetic mapping will improve diagnosis of the severity of SCI and potentially provide a fingerprint or biomarker of an individual’s regenerative status and potential. This research will provide new information on an individual’s response to injury at the cellular level, providing the medical and research community with new targets for therapy. SCI affects every afflicted individual differently; therefore, it requires a personalized therapeutic intervention. The goal of the new research program is to extend the personalization to the therapeutic interventions we provide so that every person with SCI can achieve complete functional recovery.
Chondroitin Sulfate Proteoglycan molecules
Chondroitin sulfate proteoglycan (CSPG) molecules are proteoglycans consisting of a protein core and a chondroitin sulfate side chain. They are known to be structural components of a variety of human tissues and play key roles in neural development. It is also well known that CSPGs inhibit axon regeneration after spinal cord injury and CSPGs contribute to glial scar formation post-injury, acting as a barrier against new axons growing into the injury site.
Protein tyrosine phosphatase sigma (PTPσ) has recently been identified as a receptor that binds CSPG molecules and thereby suppresses axon regeneration in response to CNS injury. However, PTPσ is also known to bind to heparin sulfate proteoglycan (HSPG) molecules, which in contrast, results in enhanced neurite outgrowth. In our study of the precise relationship between these three molecules, we hope to develop a therapy which can overcome CSPGs inhibitory effects on axonal regeneration post-injury.