The Quest Continues

More than $1 million in grants will help advance spinal-cord-injury research, as investigators search for a cure and better quality of life.

The PVA Research Foundation has announced fiscal year 2010 grant awardees. The foundation is devoted to putting grant money toward work that will advance the science needed to understand and treat spinal-cord injury and disease (SCI/D). Of the 64 applications the PVA Research Foundation’s Board of Directors received, 10 new grants were awarded, totaling $1,170,705 in funding.

Grants were awarded in three research areas. The basic science category is built on important laboratory research. Fellowships for postdoctoral scientists, clinicians, and engineers encourage training and specialization in the field of spinal-cord research. The design and development pilot program makes efforts to improve lives by broadening accessibility for people with SCI as well as the wheelchair community.

In 2002, a highly distinguished award was named for Fritz Krauth, a 40-year Paralyzed Veterans of America (PVA) member, who made a significant donation to the PVA Research Foundation. In this recent grant cycle, Rachel Cowan, PhD, at the Miller School of Medicine of the University of Miami, was awarded this distinguished fellowship award, the 2010 Fritz Krauth Memorial Fellow, for her work “Barriers & Participation after SCI: Relationship with Fitness & Mobility.”

Basic Science

Optimizing Respiratory Plasticity Following Cervical Spinal Cord Injury

Michael A. Lane, PhD

University of Florida, Gainesville

$148,790 (2 years)

The majority of SCIs occur in the neck region (cervical spinal cord). Injuries at this level often disrupt the cells and nerve fibers that control function of the diaphragm (the primary muscle of inspiration) and impair breathing. Research has shown that some spontaneous recovery can occur following partial cervical SCI, which is attributed to some spontaneous repair processes (“plasticity”). However, the extent of plasticity is limited, and long-term deficits persist.

The proposed research will improve our understanding of how plasticity contributes to recovery of breathing. Although plasticity can be temporarily enhanced with drugs, permanent improvements will likely require treatments that will repair the injured tissue. Thus, this project will use a newly discovered compound that has the potential to enhance growth of injured nerve fibers and promote repair and plasticity.

This study will significantly enhance our understanding of plasticity following SCI and will allow evaluation of an extremely novel treatment compound.  

Role of Astrocyte Glutamate Transporter GLT1 in Secondary Loss After SCI

Angelo C. Lepore, PhD

Johns Hopkins University School of Medicine, Baltimore

$150,000 (2 years)

In the majority of SCI cases, most functional loss does not result from initial trauma but is instead due to subsequent secondary injury. One of the major causes of secondary injury is excitotoxic cell death due to increased levels of the neuron-to-neuron communication molecule glutamate. Glutamate is efficiently cleared from synapses by glutamate transporters.

Astrocytes are supportive cells with crucial roles in nervous-system function. They express the major glutamate transporter, GLT1, and are responsible for the vast majority of glutamate buffering, thereby preventing excess buildup and excitotoxic injury.


Carlos B. Mantilla, MD, PhD, hopes to provide important new information regarding recovery of diaphragm-muscle function after spinal-cord injury. He is one of the 2010 PVA Research Foundation grant awardees.

This study will examine the role played by astrocyte GLT1 in secondary injury following SCI. In addition, replacement of dysfunctional astrocytes in the injured spinal cord will be targeted by transplanting astrocyte stem cells engineered to produce high levels of GLT1. This therapeutic approach aims to prevent secondary injury by reconstituting a more normal astrocytic environment in the injured spinal cord, including restoration of glutamate homeostasis.

Motoneuron Targeting for Respiratory Recovery after Spinal Cord Injury

Carlos B. Mantilla, MD, PhD

Mayo Clinic Rochester d/b/a Mayo Clinic College of Medicine, Rochester, Minn.

$150,000 (2 years)

The studies funded by this grant will provide important new information regarding the recovery of diaphragm-muscle function following SCI. More than half the people living with SCI have injuries to their cervical spinal cord.

The diaphragm muscle is the most important muscle involved in inhalation. However, in many cases of SCI it is paralyzed or seriously impaired. Following spinal-cord hemisection in rats, there is gradual (although incomplete) recovery of diaphragm-muscle function.

Our overall hypothesis is that functional recovery of diaphragm activity after spinal hemisection will be enhanced by increasing TrkB signaling in phrenic motoneurons innervating the diaphragm muscle. Our long-term goal is to develop an effective therapy to increase TrkB expression in phrenic motoneurons and thereby promote functional recovery after upper cervical SCI.

Pharmacologic Enhancement of Training Improves Recovery from Cervical SCI

Jed S. Shumsky, PhD

Philadelphia Health and Education Corporation d/b/a Drexel University College of Medicine

$150,000 (2 years)

Most human SCIs involve damage at the cervical level, which results in loss of function below the injury. Regaining arm and hand function is considered a high priority by SCI patients because this can dramatically impact their level of independence.

To develop novel combinations of interventions that might promote forelimb recovery, we reviewed stroke literature and found three promising interventions. First, forelimb motor training induces structural and functional changes throughout the motor system. Second, housing in an enriched environment provides a stimulus-rich habitat that encourages activity and promotes anatomical reorganization. Third, the psychostimulant amphetamine supports axonal sprouting and synapse formation following injury.

We hypothesize that by targeting different mechanisms, a combination of motor training, environmentally enriched housing, and amphetamine administration will stimulate neuronal plasticity and promote increased function of the injured forelimb.

Microglia Induce Myelinated Fiber Pathology Following Spinal Cord Injury

David P. Stirling, PhD

The University of Calgary, Calgary,  Alberta, Canada

$149,139 (2 years)

SCI induces a robust inflammatory response initiated in part by microglia, the resident immune cells of the brain and spinal cord. Importantly, activation of these cells following SCI may contribute to the additional loss of spinal axons and their myelin sheath, and thereby worsen neurological outcome.

This project addresses the role of microglia in SCI using highly advanced nonlinear optical imaging technology that will allow us to simultaneously record microglial activation and axon and myelin degeneration, as these events are occurring in real time following SCI. In addition, microglial modulators will be applied to inhibit their activation to investigate their role in axonal and myelin degeneration.

By identifying the key mediators that play a role in axon and myelin injury, new targets for therapeutic intervention may be discovered to preserve spinal white matter and improve neurological outcome following SCI.   

Fellowships

To Test mTOR Pathway in Axonal Regeneration and Locomotion Recovery

Duo Jin, PhD

Children’s Hospital Boston

$100,000 (2 years)

To achieve functional recovery after SCI, injured axons must regenerate past the lesion sites and reform functional connections. The main breakthrough in our lab was reported in a 2008 paper (Park et al., Science 2008), which showed that inhibiting a molecular pathway called PTEN, which is involved in cell-growth control, induces regeneration of damaged axons in the optic nerve, which carries information from the eye to the brain. 

Treadmill locomotion training has been proved to change the circuit of locomotion inside the spinal cord and improve functional recovery, which gave us a feasible way to make the regenerating be involved into locomotion circuit.

This study will test the hypothesis that PTEN deletion plus locomotion training can improve over-ground locomotion.

Barriers & Participation After SCI: Relationship with Fitness & Mobility

Rachel Cowan, PhD

Miller School of Medicine of the University of Miami, Miami, Fla.

$97,062 (2 years)

Manual-wheelchair users commonly report poor fitness and the physical environment as barriers to achieving their desired level of community participation. We propose a person’s fitness and wheelchair-propulsion ability are related to their participation, view of the environment as a barrier, and choices to avoid environmental barriers. Our long-term goal is to facilitate participation by improving fitness and/or the self-propulsion ability, thereby enabling people with SCI to independently navigate challenging environmental features.

All men and women with SCI who self-propel could benefit from this project because, regardless of injury level, fitness and propulsion skill can be improved. First, we must determine which fitness characteristic, endurance or power, best relates to participation, the ability to self-propel, perceived environmental barriers, and choices to avoid barriers.

We are also testing the quality of a new measure of self-propulsion and if it relates to participation, perceived environmental barriers, and choices to avoid environmental barriers.

Amyloid Precursor Protein Secreatases as Therapeutic Targets for SCI

Ahdeah Pajoohesh-Ganji, PhD

Georgetown University, Washington, D.C.

$100,000 (2 years)

SCI results from an initial mechanical insult on spinal-cord tissue and is followed by biochemical changes that contribute to permanent loss of sensory and motor function and long-term dysfunction. These biochemical changes can produce substances known as proteins, such as A-beta, which has been shown to increase inflammation, be directly toxic to the nervous system, and prevent the healing process. A-beta is produced via sequential cutting of a larger protein, APP, by beta and gamma secreatases.

This study will investigate the role of beta and gamma secreatases in A-beta formation and will evaluate the therapeutic value of a gamma-secreatase inhibitor after SCI. By investigating the role of APP, A-beta, and beta and gamma-secreatases after SCI, we are addressing novel therapeutic targets for SCI.

Training Novel Host-Graft Circuits to Enhance Spinal Cord Repair

Kun-Ze Lee, PhD

University of Florida, Gainesville

$100,000 (2 years)

Neuronal replacement strategies (i.e., cell transplants) may be useful for enhancing recovery after SCI, but achieving optimal “integration” between transplanted cells and the injured host spinal cord remains challenging. In addition, though future clinical transplantation approaches will be coupled with physical therapy, the potential for such rehabilitation to enhance host-graft functional interactions is unclear.

This grant directly addresses these issues by conducting electrode recordings from graft neurons in the injured cervical spinal cord. We are focusing on the cervical spinal cord because respiratory compromise is the leading cause of morbidity and mortality following SCI. Therefore, it is a high priority for basic scientists and clinicians to develop treatments to improve breathing after SCI. The overall goal is to use multidisciplinary approaches, including behavior (breathing), neurophysiology, immunohistochemistry, and neuroanatomy, to determine if a combination of cellular replacement therapy and rehabilitative training can enhance functional integration of graft neurons and respiratory motor recovery.

Design and Development

Development of Portable Transfer Technology for Boarding Boats

Dianne Goodwin, ME

Blue Sky Designs, Inc., Minneapolis

$25,000 (1 year) Pilot Funding

Portable watercraft transfer technology will allow people with mobility impairments to more safely and easily go boating and fishing. The transfer device provides a means of getting from the dock or shore into a boat. People with mobility impairments will transfer onto a platform on one end, move across a path, and get off on the other end. This lowers their center of gravity, provides stability in the transfer, and eliminates the need for others to lift and carry someone while stepping into or from an unstable boat. The device can be folded or broken down and transported in a personal vehicle or boat. This provides people with disabilities, their families, and groups more freedom of choice as to where they boat.

Development activities will build on previous concepts and focus on creating prototypes with improved functionality. Water-based tests will assess its stability and safety in use.

Partners for Progress

In addition to the work of its own foundation, PVA supports other numerous efforts in the SCI-research field. For example, at the Center for Neuroscience and Regeneration Research at Yale

University, scientists study nerve regeneration, demyelination of the nerves, and chronic pain, while member organizations of the International Campaign for Cures of Spinal Cord Injury Paralysis fund research toward a cure for paralysis. And since 1980, treatments for SCI/D complications have been studied by the PVA-endowed Professor in SCI/D Medicine at the Stanford University School of Medicine (Calif.).

For more information about the projects summarized in this article, contact PVA Research, 800-424-8200.

 

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