# The Function and Mechanisms of Autophagy in Spinal Cord Injury

> **NIH NIH RF1** · UNIVERSITY OF MARYLAND BALTIMORE · 2022 · $2,231,793

## Abstract

Project Summary
With recent advances in treatment and healthcare, life expectancy for persons following spinal cord injury (SCI)
has increased substantially for several decades after their traumatic event. Moreover, given increased falls in
the elderly, the risk of SCI has been increasing in that population. Although aging is a key risk factor for
cognitive decline and incident Alzheimer’s Disease and Related Dementia (AD/ADRD), recent large-scale
longitudinal population-based studies indicate that patients with SCI are at a high risk of dementia associated
with substantial cognitive decline. This represents an unmet health-care challenge. However, there is a lack of
information in the brain pertaining to the natural brain aging and brain aging trajectories of AD/ADRD following
SCI. Such information is needed for the design of targeted, early interventions aimed at reducing the risk of
cognitive decline after SCI. The autophagy-lysosomal pathway is essential for intracellular lipid, protein, and
organelle degradation and quality control. Impaired autophagy is strongly implicated in accumulation of
pathological protein aggregates such as phospho-tau tangles and amyloid β plaques and consequent neuronal
cell damage and death in neurodegenerative diseases. Recent data indicate that age related decline in
autophagy and lysosomal function in the brain was exacerbated by SCI. This was accompanied by increased
brain inflammation and neurodegeneration, suggesting that perturbation of autophagy may provide a
mechanistic link between SCI and AD/ADRD. Moreover, disruption of lipid homeostasis in the aged brain may
contribute to autophagy defects. We hypothesize that SCI accelerates inhibition of autophagy-lysosomal
function in the ageing brain through perturbation of lysosomal lipid homeostasis, ultimately aggravating long-
term pathological and functional outcomes and increasing posttraumatic dementia risk.
 We will use young adult and aged animals with autophagy hypomorph or heperactivation to delineate
the roles of autophagy-lysosomal pathway as a key regulator of brain pathology in SCI. HILIC-MS/MS based
lipidomics, flow cytometry, complementary microscopy and biochemical approaches will be used in AIM 1 to
determine if lipid accumulation causes lysosomal dysfunction and inhibition of autophagy in the ageing brain
after SCI. AIM 2 will determine if inhibition of precision autophagy in the ageing brain after SCI leads to
exacerbated inflammation and neurodegeneration increasing dementia risk. Using becn1 mutant mice with
autophagy heperactivation or a naturally occurring autophagy inducer trehalose in aged mice or mice aging
after SCI, AIM 3 will evaluate long-term effects of increased autophagy on proteostasis, neuroinflammation,
neurodegeneration and cognitive outcomes relevant to AD/ADRD after SCI.
 The information gained from these highly significant and innovative studies will have an important
positive impact through identifying autophagy-lysosomal...

## Key facts

- **NIH application ID:** 10439021
- **Project number:** 2RF1NS094527-06
- **Recipient organization:** UNIVERSITY OF MARYLAND BALTIMORE
- **Principal Investigator:** MARTA M LIPINSKI
- **Activity code:** RF1 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $2,231,793
- **Award type:** 2
- **Project period:** 2016-06-01 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10439021

## Citation

> US National Institutes of Health, RePORTER application 10439021, The Function and Mechanisms of Autophagy in Spinal Cord Injury (2RF1NS094527-06). Retrieved via AI Analytics 2026-06-03 from https://api.ai-analytics.org/grant/nih/10439021. Licensed CC0.

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