# Modulation of lumbar motor circuitry after an above-level SCI and NT-3 gene therapy

> **NIH NIH R01** · INDIANA UNIVERSITY INDIANAPOLIS · 2020 · $381,564

## Abstract

Spinal cord injury (SCI) is a severe medical problem experienced by humans with high mortality and long term
morbidity. Unfortunately, there has been no effective treatment available for SCI patients. The lumbar
motoneurons (MNs) are the final common pathway for motor output to the hindlimbs. Any impairment of these
MNs can cause hindlimb paralysis and muscle atrophy. When SCI occurs above the lumbar level, namely
above-level injury, the lumbar MNs are not directly damaged by the trauma, but they undergo profound
dendritic atrophy and synaptic stripping. While most SCI studies to date have focused on the regeneration or
protection of the injured spinal cord at the injury site, few studies have explored how modulation of lumbar MN
circuitry would affect pathological and functional consequences after an above-level SCI. Our goal is to
develop a beneficial restorative treatment targeting lumbar MNs after an above-level SCI and to functionally
dissect out how individual afferent pathways affect lumbar MN remodeling and functional recovery. In this
application, we propose a central hypothesis that increasing local NT-3 levels at lumbar MN pools will stimulate
the recruitment of spared axons from distinct afferent pathways and enhance their synaptic formation onto
lumbar MNs. Thus, reestablishment of neural circuitry at the lumbar level forms the anatomical basis for
hindlimb functional recovery after an above-level SCI. Accordingly, three specific aims are proposed to
investigate the three major afferent pathways to influencing lumbar MNs function to determine their roles in NT-
3-mediated remodeling of lumbar motor circuitry and hindlimb recovery after a thoracic SCI. These pathways
include the descending reticulospinal tracts (RetST), the descending propriospinal tracts (dPST), and the
dorsal roots (DR) afferents. Once the functional role of each specific pathway is defined, we will used
combinational approaches to target multiple pathways to maximize the treatment effect. This will be done u
sing
an adult mouse thoracic 9 (T9) contusive SCI model and an AAV2-NT-3 gene transfer approach to increase the
level of NT-3 in MNs.

## Key facts

- **NIH application ID:** 9994387
- **Project number:** 5R01NS103481-04
- **Recipient organization:** INDIANA UNIVERSITY INDIANAPOLIS
- **Principal Investigator:** George M Smith
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $381,564
- **Award type:** 5
- **Project period:** 2017-09-30 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9994387

## Citation

> US National Institutes of Health, RePORTER application 9994387, Modulation of lumbar motor circuitry after an above-level SCI and NT-3 gene therapy (5R01NS103481-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9994387. Licensed CC0.

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