# The Function and Mechanisms of Autophagy in Spinal Cord Injury

> **NIH NIH R01** · UNIVERSITY OF MARYLAND BALTIMORE · 2020 · $337,969

## Abstract

PROJECT SUMMARY
 A major barrier to development of novel treatments against spinal cord injury (SCI) is incomplete
understanding of the mechanisms of injury and recovery. The overall aim of our research is to determine the
molecular mechanisms and contribution of autophagy to neuronal cell damage and death after SCI, in order to
allow future development of rational therapies. Autophagy is a lysosome-dependent degradation pathway
essential for normal cellular homeostasis and protection from neurodegeneration. However, when lysosomal
function is compromised autophagy can also contribute to cell death. Accumulation of autophagosomes has
been noted after SCI, but its mechanisms and function remain unknown. Additionally, lysosomal function and
the efficiency of autophagic degradation (flux), has not been assessed after SCI. Based on our preliminary
data, we propose and will test the hypothesis that early after SCI dysfunction of the autophagy-lysosomal
pathway contributes to neuronal cell damage and death and its restoration can promote long-term recovery.
 We will use autophagy-reporter and autophagy-deficient transgenic mice and in vivo and in vitro
pharmacological and genetic manipulations to determine the mechanisms of autophagy after SCI and
demonstrate its influence on neuronal cell death and functional outcomes after SCI. AIM 1 will determine the
mechanisms of lysosomal and autophagy dysfunction after SCI. Complimentary in vivo and in vitro
approaches will be combined with novel techniques such as ex vivo spinal cord slice cultures to test the
hypothesis that autophagy flux is impaired early after SCI, reflecting cytoplasmic phospholipase A2 (cPLA2)
mediated lysosomal membrane permeabilization (LMP). AIM 2 will determine functional consequences of
restoring autophagy-lysosomal pathway after SCI. Pharmacological inducers of lysosomal biogenesis and
autophagy flux, Trehalose and Torin1, will be used in wild type and autophagy deficient Becn1+/- mice to test
the hypothesis that stimulating lysosomal biogenesis will restore autophagy-lysosomal pathway and result in
improved functional outcomes. AIM 3 will determine the influence of autophagy-lysosomal pathway on
axonal damage and neuronal cell survival after SCI. The contribution of impaired autophagy to axonal
damage and neuronal cell death after SCI will be examined in vivo; we will also determine whether improving
autophagic flux can attenuate neuronal cell damage and death after SCI. We hypothesize that impaired
autophagy flux contributes to ER stress induced axonal damage and neuronal apoptosis after SCI.
 Our study will for the first time determine the function and the mechanisms of autophagy in neuronal cell
damage and death after SCI. Additionally we will determine the optimal approaches for manipulation of
autophagy-lysosomal pathway to improve functional outcomes after SCI, thus opening potential novel
treatment avenues.

## Key facts

- **NIH application ID:** 9931298
- **Project number:** 5R01NS094527-05
- **Recipient organization:** UNIVERSITY OF MARYLAND BALTIMORE
- **Principal Investigator:** Junfang Wu
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $337,969
- **Award type:** 5
- **Project period:** 2016-06-01 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9931298

## Citation

> US National Institutes of Health, RePORTER application 9931298, The Function and Mechanisms of Autophagy in Spinal Cord Injury (5R01NS094527-05). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9931298. Licensed CC0.

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