# Respiratory Dysfunction in an Optineurin knock out ALS mouse model

> **NIH NIH R21** · DUKE UNIVERSITY · 2020 · $442,750

## Abstract

7. PROJECT SUMMARY/ABSTRACT
Amyotrophic Lateral Sclerosis (ALS) is a devastating and fatal neurodegenerative disease with no current cure.
Focal weakness eventually progresses to global muscle weakness and paralysis, but the exact etiology of these
events remains unknown. Many patients die when they ultimately succumb to inadequate ventilation, hypoxia,
and respiratory failure. Recently, the gene for optineurin (OPTN) was found to be associated with
neurodegeneration in ALS. Patients with OPTN mutations show an onset of ALS from 30 to 60 years of age and
have a slowly progressive disease before they eventually die of respiratory failure. The etiology of OPTN
deficiency induced respiratory failure remains unknown and will be a focus of Aim 1 of this application. In addition,
in Aim 2, we will look at the impact of hypoxia (or low oxygen levels) on disease initiation and progression. In
ALS, impaired breathing due to progressive weakness of the respiratory muscles leads to chronic intermittent
hypoxia. However, prior to diagnosis, we propose that hypoxia may also play a role in triggering the disease
onset and exacerbating motor weakness in OPTN deficient patients. At the cellular level, hypoxia induces
mitochondrial degradation, activates autophagy and induces cell death. Interestingly, OPTN regulates
mitochondrial degradation, autophagy and cell death. Since OPTN is essential in regulating autophagy, we
propose that in the absence of OPTN, the effects of chronic intermittent hypoxia (CIH) will be amplified and will
result in protein aggregation and cellular disruption in respiratory motoneurons. This disruption will further
exacerbate breathing impairment. Thus, the fundamental hypothesis driving this proposal is that OPTN
deficiency impairs respiratory function, and exposure to CIH triggers early disease onset and
accelerates respiratory pathology. In order to test our hypothesis, we will use OPTN knock out mice (Optn-/-)
generated by Henry Tseng (co-I). Similar to pathology experienced by ALS patients, these mice exhibit deficits
in balance, coordination, and motor impairment that progressively deteriorates with age. Optn-/- mice provide an
important opportunity and an ideal tool to study stress-dependent mechanisms that exacerbate
neurodegeneration and respiratory function in ALS. Two specific aims will be accomplished using the Optn-/-
mouse model: Aim 1: To identify the impact of OPTN deficiency on respiratory function and respiratory
motoneurons, nerves, and muscle in ALS and Aim 2: To assess the impact of CIH on disease onset and
progression in OPTN deficiency. The proposed experiments address a comprehensive evaluation of respiratory
function including spontaneous breathing and respiratory nerve output, as well as biochemical and histological
assessment of respiratory motor units. This R21 proposal will combine the respiratory physiology and ALS
mouse model experience of the PI (ElMallah), with the neurobiology and optineurin experience o...

## Key facts

- **NIH application ID:** 9978360
- **Project number:** 1R21NS112781-01A1
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** Mai ElMallah
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $442,750
- **Award type:** 1
- **Project period:** 2020-04-01 → 2022-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9978360

## Citation

> US National Institutes of Health, RePORTER application 9978360, Respiratory Dysfunction in an Optineurin knock out ALS mouse model (1R21NS112781-01A1). Retrieved via AI Analytics 2026-06-12 from https://api.ai-analytics.org/grant/nih/9978360. Licensed CC0.

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