# Investigations into ASIC1a-dependent neuronal death

> **NIH NIH R01** · OHIO STATE UNIVERSITY · 2021 · $377,848

## Abstract

The acid sensing ion channel1a (ASIC1a) is essential for normal brain function, but initiates neuronal death
and contributes to ischemic brain injury. Prolonged reductions in extracellular pH accompany ischemia and
ASIC1a inhibition limits neurological damage. Yet, ASICs also play an important role in normal physiology and
established models of ASIC-induced cell death make it difficult to develop strategies that specifically inhibit
ASIC1a toxicity. Our preliminary data support a newer model of ASIC1a-induced cell death. Specifically, we
have discovered that the toxic effect of ASIC1a can be eliminated by modification of the intracellular region of
the channel or activation of the delta opioid receptor (DOR). An especially provocative aspect of these
findings is that acidotoxicity is inhibited without a reduction in ASIC1a current, thereby suggesting that the
toxic and physiological actions of the channel can be separated. Our central hypothesis is that DOR prevents
acidotoxicity through signaling cascades, which act on the intracellular domain of ASIC1a to limit protein
interactions required for toxicity. To test this hypothesis, we will define the mechanisms governing DOR action
on ASIC1a and elucidate their role in ischemic injury in vivo. The outcomes of the proposed work will reveal
novel regulatory mechanisms controlling ASIC1a-induced toxicity, suggest new interventions to mitigate
ASIC-induced death using existing DOR agonists, and reveal strategies to separate the physiological and
pathological actions of ASIC1a. These results will be significant as they are expected to have broad
implications for the prevention of brain injury following ischemic stroke as well as other disorders where
neuronal acidotoxicity plays a role.

## Key facts

- **NIH application ID:** 10215637
- **Project number:** 5R01NS112805-02
- **Recipient organization:** OHIO STATE UNIVERSITY
- **Principal Investigator:** CANDICE C ASKWITH
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $377,848
- **Award type:** 5
- **Project period:** 2020-07-15 → 2026-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10215637

## Citation

> US National Institutes of Health, RePORTER application 10215637, Investigations into ASIC1a-dependent neuronal death (5R01NS112805-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10215637. Licensed CC0.

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