Spinal cord injury (SCI) is a debilitating condition that results in significant loss of motor function and reduction in quality of life for the approximatel 265,000 Americans affected. For many years, a dogma held by those studying SCI was that long-range regeneration of descending tracts was the key to regaining function. However, more recent research has shown that functional recovery is due to local rewiring of these tracts to propriospinal neurons and plasticity of spared neural tissue within the spinal cord. To better understand how this regeneration occurs, we need to identify which neuronal populations are involved in these local rewiring events after SCI. While the local circuitry that contributes to locomotion via central pattern generators is well defined in model organisms, the full details of the interneuron (IN) circuitry contributing to rhythm generation and frequency modulation are still being defined in mammals. Currently, very few examples exist with firm links between developmental identity, as assessed by molecular and/or transcription factor profiles, and functional identity, as assessed by electrophysiology and/or connectivity patterns. New tools are needed to better understand the role of different spinal INs populations in functional recovery after SCI and to develop potential interventions to target these populations. This project will develop tools to isolate and culture ventral spinal neuron populations. We will develop an in vitro platform that will allow us to study connectivity between INs, motoneurons (MNs), and cortical neurons in a model system and to define cues that promote functional connectivity of these networks. Finally, we will examine the contributions of transplanted spinal MN and IN populations to functional recovery in a rat model of spinal cord injury.

Public Health Relevance

Statement Spinal cord injury is a major clinical problem; about 12,000 new injuries are added annually to the approximately 265,000 spinal cord injury patients in the United States. Mechanistic knowledge gained and therapeutic approaches developed in this study may contribute to future clinical therapies for spinal cord injury patients Transplantation approaches using spinal cord neurons developed in this project may also be useful for other neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS).

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS090617-04
Application #
9463796
Study Section
Bioengineering of Neuroscience, Vision and Low Vision Technologies Study Section (BNVT)
Program Officer
Jakeman, Lyn B
Project Start
2017-02-01
Project End
2020-01-31
Budget Start
2018-02-01
Budget End
2019-01-31
Support Year
4
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Texas Austin
Department
Biomedical Engineering
Type
Biomed Engr/Col Engr/Engr Sta
DUNS #
170230239
City
Austin
State
TX
Country
United States
Zip Code
78759
Thompson, Russell; Sakiyama-Elbert, Shelly (2018) Using biomaterials to promote pro-regenerative glial phenotypes after nervous system injuries. Biomed Mater 13:024104
Zholudeva, Lyandysha V; Qiang, Liang; Marchenko, Vitaliy et al. (2018) The Neuroplastic and Therapeutic Potential of Spinal Interneurons in the Injured Spinal Cord. Trends Neurosci 41:625-639
Thompson, Russell E; Pardieck, Jennifer; Smith, Laura et al. (2018) Effect of hyaluronic acid hydrogels containing astrocyte-derived extracellular matrix and/or V2a interneurons on histologic outcomes following spinal cord injury. Biomaterials 162:208-223
Pardieck, Jennifer; Sakiyama-Elbert, Shelly (2018) Genome engineering for CNS injury and disease. Curr Opin Biotechnol 52:89-94
Zholudeva, Lyandysha V; Iyer, Nisha; Qiang, Liang et al. (2018) Transplantation of Neural Progenitors and V2a Interneurons after Spinal Cord Injury. J Neurotrauma 35:2883-2903
Thompson, Russell E; Lake, Allison; Kenny, Peter et al. (2017) Different Mixed Astrocyte Populations Derived from Embryonic Stem Cells Have Variable Neuronal Growth Support Capacities. Stem Cells Dev 26:1597-1611
Iyer, Nisha R; Wilems, Thomas S; Sakiyama-Elbert, Shelly E (2017) Stem cells for spinal cord injury: Strategies to inform differentiation and transplantation. Biotechnol Bioeng 114:245-259
Iyer, Nisha R; Huettner, James E; Butts, Jessica C et al. (2016) Generation of highly enriched V2a interneurons from mouse embryonic stem cells. Exp Neurol 277:305-316
Xu, Hao; Sakiyama-Elbert, Shelly E (2015) Directed Differentiation of V3 Interneurons from Mouse Embryonic Stem Cells. Stem Cells Dev 24:2723-32
Wilems, Thomas S; Pardieck, Jennifer; Iyer, Nisha et al. (2015) Combination therapy of stem cell derived neural progenitors and drug delivery of anti-inhibitory molecules for spinal cord injury. Acta Biomater 28:23-32

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