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Delivering Discoveries

Reprinted from PN/Paraplegia News April 2018

PVA’s 2018 Research Foundation grant recipients are aiming to find out how to improve the lives of people living with SCI/D.

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When the Paralyzed Veterans of America (PVA) Research Foundation was established in 1976, the primary research question was “if” the spinal cord could be  reconnected or regenerated. Over the years, the question has changed from “if” to “when” it would happen, as researchers investigated different strategies and techniques to address the problem. Today, the question is not “if” or “when,” but “how?” According to Ona Bloom, PhD, spinal-cord injury (SCI) researcher and professor at the Feinstein Institute for Medical Research and  Zucker School of Medicine at Hofstra/Northwell in New York, there are several strategies that researchers are currently testing, alone or in combination, to learn how to help nerves regenerate and/or function better after SCI or other conditions that may lead to paralysis.   One key strategy is neuroprotection, which means to protect nerve cells from dying after they have been damaged. An example of this might be a drug that weakens toxic inflammatory signals that may arise as part of the body’s wound-healing response. Another strategy is neuroplasticity that aims to promote growth of nerve cells that remain alive to make new connections. An example of this might be a special nutrient added to nerve cells or perhaps even a new rehabilitation program.  The third major strategy is to replace damaged nerve cells with completely new ones, otherwise known as cell transplantation. Since the brain and spinal cord need to work together to accomplish many activities of daily living, some of these strategies are being tested in the brain, some in the spinal cord and some in both places. 

There is also an effort to incorporate cutting-edge engineering technology into the field, as new devices are being tested to see if they help promote neuroplasticity in rehabilitation programs or as assistive devices to help people live more independently. With these ideas in mind, the PVA Research Foundation has selected the 2018  grant recipients whose research will help answer the question, “How?” The foundation awarded just over $1 million to fund the following eight research studies over the next two years. Funding for this grant program comes from PVA chapters, members, family members and other donors who want to improve the lives of paralyzed veterans and their families. Grants are awarded in four categories: basic science, clinical, design and development and fellowships. The following are brief descriptions of the 2018 grant awardees and their respective studies.

Basic Science

Connectivity Mapping of Neural Stem Cells for Restoring Locomotor Function

Jennifer Dulin, PhD

Texas A&M University

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$145,498

Neural stem cells transplanted into sites
of SCI give rise to new neurons that can replace lost spinal-cord tissue. These graft-derived neurons integrate into the injured adult nervous system, forming new neural circuits with potential to restore lost neurological function. 
However, there are many different subtypes of graft-derived neurons, and it remains unclear which of these are most critical for restoring specific circuits. The overall goal of this project is to define the key classes of graft-derived neurons that are best equipped to restore locomotor circuitry after SCI. Researchers will identify specific neuron classes that directly synapse onto host spinal-cord motor neurons and test whether these subtypes can transmit descending motor signals across sites of complete SCI. In this way, this project will establish a new framework defining the most functionally important types of graft-derived neurons with potential to improve motor outcomes.

Enhancing Axon Growth and Function by Translatable OPN/IGF1 Treatment Post SCI

Yuanyuan Liu, PhD

Children’s Hospital at Boston

$150,000

A key pathology following SCI is the permanent local breakdown of descending axons that connect the brain and spinal cord. A promising repair strategy would be to promote the regrowth of those descending axons across the injury.  In a previous study, researchers demonstrated that virus-mediated expression of osteopontin and insulin-like growth factor (IGF1) promoted the regrowth of brain-derived corticospinal tract (CST) axons and functional recovery of CST-dependent motor function following an incomplete SCI lesion. Here, researchers will use a blood-brain barrier-penetrating virus vector to overexpress osteopontin and IGF1 in most neurons and assess its effects on anatomical and behavioral outcomes aside from the CST. In addition, researchers will test if more translatable delivery of recombinant osteopontin and IGF1 proteins using multifunctional fibers can achieve similar restoration after SCI. The proposed experiments would generate highly translatable results for designing repair strategies for SCI patients.

Manipulating Corticospinal Growth State and Axon Guidance For Motor System Repair


John Martin, PhD

City University of New York

$150,000

The aim of this proposal is to develop a novel strategy to repair the corticospinal tract (CST) after cervical spinal injury in the mouse. The CST is the principal motor control pathway for skilled voluntary movements. Researchers will take a dual brain stimulation and genetic approach to repair the CST. Investigators stimulate the motor cortex to activate a CST growth program to promote axon sprouting after injury. The genetic approach eliminates particular genes after SCI to help establish novel connections between the newly sprouted CST axons and spinal-cord motor neurons. If successful, this will be the first SCI repair strategy to rebuild elements of the CST circuit after injury.

Clinical 

A Metabolomics Approach to
Diagnose Multiple Sclerosis

Robert Powers, PhD

University of Nebraska

$150,000

Multiple sclerosis (MS) treatments are time-sensitive and require early intervention to impede the accumulation of disabilities
and to improve the long-term prognosis of an MS patient. 
Unfortunately, a correct diagnosis of MS is commonly delayed (upwards of years) because of MS’s similarity to numerous other diseases and the diversity of symptoms experienced by MS patients.  But by far, the overwhelming reason for routine delays in obtaining a correct diagnosis of MS is the complete lack of a simple, accurate and efficient diagnostic protocol. Instead, diagnosing MS is challenging and error-prone, relying on a complex combination of expensive, invasive and risky tests and difficult patient observations. To remedy this problem, the researchers propose to identify a unique chemical fingerprint in a patient’s urine sample to provide a reliable and early diagnosis test for MS and to help guide personalized treatments for MS patients.

Design & Development 

Intelligent Assistive Robot Arm 

Henny Admoni, PhD

Carnegie Mellon University

$150,000

Wheelchair-mounted assistive robot arms provide a flexible, mobile and highly dexterous tool that enables people with upper motor impairments to eat, drink and care for themselves independently. However, controlling a robot arm can be difficult for people with motor impairments, who may only be able to use limited input devices (like a joystick or a sip-n-puff) to operate the robot. This project develops a robot arm that uses people’s natural, subconscious nonverbal behaviors to help predict what kind of assistance they need. Based on eye gaze and other behaviors, the system infers a user’s intentions and when he or she is having difficulty with a task. State-of-the-art shared autonomy algorithms can then use these predictions to provide seamless robot assistance for completing tasks more quickly and with less effort. This project may help transform the way people use assistive robots, facilitating their re-entry into mainstream society and increasing their quality of life.

Fellowships

Bioactive Peptide Amphiphile Scaffolds to Enhance Spinal-Cord Regeneration

Zaida Alvarez Pinto, PhD

Northwestern University

$100,000

SCI is a debilitating condition affecting an estimated 1.3 million Americans and costing over $40 billion each year. SCI causes immediate damage of neural tissue at the site of injury, which impedes functional tissue repair and limits possible therapeutic approaches. Previously, the Stupp Laboratory at Northwestern University in Evanston, Ill., demonstrated that synthetic nanofiber materials could be used as noninvasive injectable bioactive implants and showed enhanced regeneration in an experimental mouse model of SCI. Here, the applicant proposes a combinatorial approach that integrates multiple bioactive signals displayed on the nanofiber scaffold to address various aspects of the injury and increase the potency of the bioactive materials. Designing and testing materials with specific signals that limit the spread of damage and promote revascularization, nerve regeneration and functional recovery after SCI will accomplish this goal.

Clarifying the Mechanism Underlying Hyperreflexia After SCI

Curtis Benson, PhD

Yale University & the Department of Veterans Affairs Connecticut Healthcare System

$100,000

Spasticity is a frequent complication related to over-activity in the spinal-cord reflex system after SCI. Daily life with spasticity can be extremely difficult, affecting movement and speech, and in some cases, the condition can be painful. Current treatments for spasticity are “hit-or-miss,” may have negative side effects and long-term use can worsen outcomes. The purpose of this project is to 1) better understand the underlying cause of spasticity, and 2) assess a novel gene therapy to alleviate the spastic condition. The researchers hypothesize that reducing the activity of a key molecular target responsible for abnormal neuroplasticity using a gene therapy will reduce spasticity. Gene therapy is an emerging medical technology with unique advantages compared with conventional drugs, including reduced side effects and long-lasting effectiveness. Successful project completion will greatly improve the understanding of spasticity and provide novel opportunities for developing more effective and safe treatments for spasticity after SCI.

Cortical Plasticity After Spinal-
Cord Injury

Hang Jin Jo, PhD

University of Miami Miller School of Medicine

$100,000

Several neuromodulatory therapies are currently used in humans with SCI, alone or in combination with training to promote hand motor recovery. Although these approaches have resulted in improvements in hand voluntary motor output and other related body functions, it is clear that the improvements are limited and there is a need to develop novel interventions. Here, a new approach will be proposed that targets cortical connections to spared descending motor pathways as a mechanism for recovery. Researchers will use a motor task together with noninvasive-paired cortical stimulation to target corticospinal descending volleys during gross grasping behaviors in humans with and without SCI.

For more information on the PVA Research Foundation, visit pva.org.

Cheryl Vines is PVA’s director of research and education.

 

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