Ongoing Research Projects
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The RIRC is a basic science research facility devoted to studying cellular and molecular mechanisms that underlie the response of the nervous system to injury, exploring innate and therapeutic regenerative capabilities and developing treatments for SCI. The RIRC has 4 principal investigators (PI's) whose labs are located in the Center whose research focuses on the use of rodent models (rats and mice) and related cell culture systems to study how the spinal cord responds to injury. A major focus is on enhancing the regeneration of damaged nerve fibers (axon regeneration) and on the use of stem cells for cellular replacement therapy. There are also 23 Associate PI's whose labs are located elsewhere in the University who study the response to injury, neural repair, regeneration, and stem cell biology. Some of the Associate Investigators also carry out human subjects research focusing on advanced functional imaging techniques, novel rehabilitative strategies including the use of robotics, advanced prosthetics, and associated devices that are capable of recording signals from the nervous system.
There are a number of potential targets for therapy for SCI, and scientists at the RIRC address many of these. Importantly, some of the most promising strategies, and the ones that are closest to clinical application, involve interventions during the acute post-injury period (days to weeks after the injury). However promising these strategies are, we are committed to the long-term goal of developing treatments to promote nerve regeneration and repair for individuals with chronic injuries, and this is reflected in the research programs of each PI.
The full scope of the research can best be appreciated by consulting the research summaries of the individual PI's. Here, we highlight the general themes, and provide a roadmap for navigating through the more detailed descriptions.
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Limiting the secondary degeneration that occurs after spinal cord injury
After the initial trauma to the spinal cord, several processes occur that actually make the injury worse. Chemicals released from damaged cells, including the neurotransmitters nerve cells use to communicate with one another, are toxic when released in large quantities and cause the death of nerve cells that might otherwise survive. These toxins produce a wave of secondary damage during the first hours and days after the injury. Then, the body reacts with an immune response that involves an influx of inflammatory cells that clean up the debris from dying cells. This response is part of the healing process, but can also cause secondary damage over the first 1-2 weeks after the injury as the inflammatory cells release molecules to digest degeneration debris. Other processes that are less well-understood lead to a slow progressive degeneration of nerve cells as well as the supporting cells that form the myelin sheath, which continues for weeks and even months.
An important target for therapy involves approaches that seek to limit this secondary degeneration. Examples of these approaches include studies of the mechanisms of "excitotoxic" cell death, which results from the un-controlled release of neurotransmitters (Os Steward, John Weiss), and studies of the critical chemical signals that control the inflammatory response (Aileen Anderson, Hans Keirstead, Tom Lane).
Enhancing regeneration of damaged nerve cells
The loss of motor and sensory function following spinal cord injury is due to the interruption of the long nerve connections (tracts) between the brain and the spinal cord. Accordingly, full restoration of function will require that we find ways to induce these damaged connections to regenerate. In very young organisms, regeneration does occur, but the ability to regenerate nerve connections is lost as development proceeds. The reasons for regenerative failure include: 1) loss of the intrinsic capacity for growth by neurons due to shutting down key genes that are required for growth; 2) presence of inhibitory molecules in the myelin sheath of axons that blocks regenerative growth; 3) the development of a dense glial scar at the injury site that contains molecules that are strongly inhibitory to growth; and 4) lack of a tissue environment that is supportive for growth.
Each of these represent important potential targets for therapy following spinal cord injury. For example, one approach is to stimulate growth by turning on key genes, including "growth factors", that are required for regeneration and the formation of connections between neurons (known as "synapses"). Of particular interest are "activity-regulated genes" that can be induced by manipulating neuronal activity (Os Steward, Carl Cotman, Christine Gall).
An important area of regeneration research involves identification of inhibitory molecules present in the myelin sheath, and the receptors on nerve cells that mediate growth inhibition (Os. Steward, Ranjan Gupta, Melanie Cocco, Noo Li Jeon). This identification is the basis for developing small synthetic molecules that could block the activation of the receptor that would otherwise cause growth inhibition, and thus promote regeneration. Another approach uses a novel immunological technique to temporarily destroy the myelin sheath in the areas near a spinal cord injury in order to promote nerve regeneration (Hans Keirstead). Dr. Keirstead has used his innovative technology, on which he holds a patent, to show that it is possible to promote axon regeneration in the spinal cord of experimental animals by temporarily removing myelin.
An important part of the healing process is the formation of a "scar" at the injury site, which restores the critical barrier between the central nervous system (in this case the spinal cord) and the periphery. At the same time, however, the cells that form this scar and that participate in "wound healing" also express molecules that are strongly inhibitory to axon growth. Understanding the mechanisms of scar formation, particularly the activity of glial cells called "astrocytes" may point the way toward interventions to block their inhibitory action without interfering with their critical role in wound healing (Os Steward, Hans Keirstead, Aileen Anderson).
Finally, to address the problem of a lack of a tissue environment that is supportive for axon growth, several RIRC investigators are exploring how transplants might be used to support regeneration. Approaches include transplants of peripheral nerve tissue (peripheral nerves are capable of some regeneration) Schwann cells (the cells in the peripheral nerve that express molecules supportive for growth), matrices made up of molecules from lower species (fish) that can regenerate, olfactory ensheathing cells from the nose, and embryonic stem cells (Ranjan Gupta, Aileen Anderson, Hans Keirstead, Lisa Flanagan, and Os Steward).
These studies in an SCI context are supplemented by studies of lower vertebrates (fish and frogs) that are capable of nerve and tissue regeneration (Ron Meyer, Susan Bryant) and studies of areas of the brain that are capable of "neurogenesis" (the birth of new nerve cells) including the olfactory bulb (Ann Calof).
Human Embryonic Stem cells
Embryonic stem cells have the ability to become any of the body's cell types, and so offer tremendous promise for treating many degenerative diseases and nervous system injuries. Scientists in the RIRC are playing a lead role in the overall effort at UCI to develop stem cell therapies for neurological disorders. Indeed, two RIRC PI's (Director Os Steward and Associate Susan Bryant) are members of the Independent Citizen's Oversight Committee (ICOC) that oversees the California Institute for Regenerative Medicine (CIRM) established through Proposition 71, and is responsible for determining the distribution of funds from Proposition 71. Os Steward was appointed by Governor Schwarzenegger as the representative for spinal cord injury, and Susan Bryant is the representative for UCI on the ICOC.
UCI intends to build a major Stem Cell Research Facility that will focus on the use of human embryonic stem cells for Neurological Disorders. This facility will be housed in a state of the art research facility that will be constructed using state funds, private donations, and funds from Proposition 71. RIRC members Hans Keirstead and Steve Cramer, along with Peter Donovan, are interim co-directors of UCI's Stem Cell Program.
In the case of spinal cord injury, embryonic stem cells could eventually be used to replace nerves that have been directly destroyed, create a tissue environment that is supportive for axon regeneration, and replace the myelin forming cells that allow signaling along surviving axons. Interestingly, it is actually the latter approach that is closest to fruition. Dr. Keirstead is working in collaboration with Geron Corporation of Menlo Park, California. Geron owns several of the federally approved human embryonic stem cell lines. Dr. Keirstead developed the protocol to turn human embryonic stem cells into oligodendrocytes, the insulation makers of the central nervous system, with a high degree of purity.
Another approach involves the transplantation of cells that are determined to become cells of the nervous system (nerve cells and glia) but not a particular cell type. These are called "neural stem cells", and are derived from young fetuses rather than blastocysts as is the case with embryonic stem cells. The hope is that these cells may re-establish some of the circuitry that is important for neural function when transplanted into the spinal cord. Dr. Aileen Anderson is working with a company called Stem Cell, Inc. to develop these neural stem cells for SCI applications by testing their function in rodent SCI models.
Improving Motor Recovery
One of the most important discoveries in the last decade is that function after spinal cord injury can be greatly enhanced by training. The injured spinal is capable of learning, and studies of the basic cellular mechanisms of this form of memory may lead to important new therapeutic strategies. Also, finding ways to "teach" the injured spinal cord more effectively will maximize the potential for recovery. RIRC investigators are developing new assessment techniques for measuring recovery, especially of upper extremity function, following spinal cord and brain injury (Kim Anderson, Steve Cramer), as well as developing novel rehabilitation strategies involving robotic applications (David Reinkensmeier). Dr. Reinkensmeyer, an aerospace engineer, is specifically interested in the area of biomechatronics, or the use of intelligent electromechanical systems to diagnose, treat and support affected functions of the human body. He and his team have developed a robot that helps to retrain arm movements. The device supports the arm and basically removes gravity, and then uses a video game to repeat different movements, strengthening muscles and neural connections. Dr. Reinkensmeyer is also collaborating with researchers at California State University at Los Angeles and UCLA to develop a robot that coordinates walking training.
Autonomic Function and Pain
The loss of bowel, bladder, and sexual function, autonomic dysreflexia, and chronic pain are some of the most important consequences of SCI. Indeed, according to a recent survey by RIRC member Kim Anderson, people with SCI reported that return of bowel / bladder and sexual function would most improve quality of life. Motivated by Dr. Anderson's findings, investigators the RIRC are attempting to address these other SCI-related problems that are less obvious to able bodied individuals, including bladder function, autonomic dysreflexia, and chronic pain (Barry Duel, Kim Anderson, Aileen Anderson, Os Steward, Hans Keirstead, David Luo).
The RIRC: Promoting Collaboration and Cooperation
In addition to the team of scientists and physicians on site at the RIRC and UCI, the Center is also a node in a network of SCI investigators that span the globe. The RIRC coordinates the Roman Reed Spinal Cord Injury Fund of the State of California. The Roman Reed Core Laboratory is an important site that supports collaborative studies between investigators from different institutions in California. The RIRC is also one of the 2 Facilities of Research Excellence in Spinal Cord Injury (FOR-SCI) designated by the National Institutes of Health, which is part of a network that carries out replications of experiments reporting novel treatments or therapies. Scientists at the RIRC (Os. Steward, Hans Keirstead, and Maura Hofstadter) are also participants in the consortium of investigators, led by Mark Tuszynski of UCSD, who are developing primate models that can be used for pre-clinical testing of new therapies in preparation of human clinical trials. More detailed descriptions of these programs can be found elsewhere in the website.