# microRNA regulation of NMNAT-mediated Neuroprotection against Peripheral Neuropathy and Chronic Pain

> **NIH NIH R33** · UNIVERSITY OF CHICAGO · 2024 · $410,000

## Abstract

PROJECT SUMMARY
 Peripheral neuropathy and neuropathy pain can be caused by a myriad of genetic and environment
factors as well as therapeutic or recreational drug use. Chemotherapy-induced peripheral neuropathy (CIPN) is
the major dose-limiting neurotoxic side effect of standard chemotherapy regiments. Over 68% of cancer patients
experience neuropathic symptoms after chemotherapy, and that contributes to a significant percent of the
population that suffer from chronic pain and often resort to opioid use. Peripheral neuropathy is closely
associated with Alzheimer’s related dementia. Specifically, a negative correlation between the severity of
peripheral neuropathy and cognitive performance has been reported in patients with dementia. The mechanisms
of CIPN and Alzheimer’s related neuropathy intersect at the dysregulation of neuronal microtubules. CIPN is
caused by microtubule-targeting chemo drugs, while a major pathology in AD is the dysregulation of microtubule
associated protein Tau (tauopathy). There is an urgent need to understand the in vivo mechanisms of CIPN and
AD related peripheral neuropathy. Recently, we have optimized a model of peripheral neuropathy using
Drosophila larvae that recapitulates salient behavioral, physiological, and cellular aspects of sensory dysfunction.
Our work using this model has uncovered a new mechanism underlying peripheral neuropathy and identified a
neuroprotective protein NMNAT with promising potential for mitigating neuropathic pain. Our preliminary studies
have identified several natural compounds that potentially upregulate NMNAT transcription and discovered the
exciting role of microRNAs in regulating both the pre-mRNA splicing and mature mRNA stability. The aims of
the parent R33 grant include, (1) test the neuroprotective activity of 9 microRNAs that regulate nociceptive
hypersensitivity and pain, (2) characterize the molecular pharmacology of 13 natural compounds in regulating
NMNAT expression and enhancing neuroprotection against peripheral neuropathy and chronic pain. The
objectives for the supplement application are to expand our testing portfolio to include genetic models of
Alzheimer’s disease and identify microRNAs and natural compounds that mitigate peripheral neuropathy in AD.
We have established Tauopathy models that recapitulate cellular pathology of Alzheimer’s including filamentous
accumulation of hyperphosphorylated Tau (pTau), neuronal degeneration, impaired nervous system physiology,
and shorted survival. Our preliminary pain behavior studies in AD models have observed a hypersensitivity to
pain in mutant hTau (hTauR406W) expressing nociceptors, consistent with clinical presentation of peripheral
neuropathy in AD patients. We propose to test our hypothesis that the neuronal microtubule dysregulation in
nociceptor neurons is a shared cellular mechanism underlying CIPN and AD induced pain. The proposed
supplement work is within the scope of the parent R33 project but expands the outcome ...

## Key facts

- **NIH application ID:** 11135937
- **Project number:** 3R33AT010408-05S1
- **Recipient organization:** UNIVERSITY OF CHICAGO
- **Principal Investigator:** Rong Grace Zhai
- **Activity code:** R33 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $410,000
- **Award type:** 3
- **Project period:** 2024-07-10 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11135937

## Citation

> US National Institutes of Health, RePORTER application 11135937, microRNA regulation of NMNAT-mediated Neuroprotection against Peripheral Neuropathy and Chronic Pain (3R33AT010408-05S1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/11135937. Licensed CC0.

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