# Regulation of Schwann Cell Mitochondria Homeostasis in Painful Peripheral Neuropathy

> **NIH NIH R21** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2023 · $434,500

## Abstract

PROJECT SUMMARY
Peripheral neuropathies have heterogeneous etiologies and can emerge from traumatic, metabolic and
chemotherapy induced events. Neuropathic pain is a major symptom of peripheral neuropathies, which is
characterized by spontaneous pain, burning and paresthesia. Often it is associated with devastating losses of
quality of life. Currently, treatments are limited and burden patients with side effects and addiction. Identifying
novel strategies for pain treatment addresses a substantial unmet medical need. Research in mechanisms of
painful peripheral neuropathy (PPN) has largely focused on sensory neurons, however, peripheral glia, Schwann
cells (SCs), emerge as an essential component of the functional unit with sensory neurons that regulate pain
states. Yet, mechanisms underlying SC contributions to PPN are largely unknown. Mitochondria dysregulation
in neurons has been identified as a mechanism associated with PPN. Although, two studies show that genetic
deletion of a key mitochondrial protein elicits a progressive demyelinating neuropathy, there are no studies
linking a SC repair receptor signaling pathway (which could be targeted therapeutically) with mitochondria
heterogeneities and/or homeostasis in SCs, relevant to neuropathic pain. We identified the low-density
lipoprotein receptor related protein (LRP1) as a key SC repair receptor after injury. An important property of
LRP1 is its ability to regulate lipid metabolism and glucose homeostasis, and therefore, control cellular
bioenergetics. We propose that LRP1 directly regulates mitochondrial dynamics and function in SCs to optimize
bioenergetic homeostasis in peripheral nerves. Our prior work investigating SC LRP1 in neuroinflammation and
pain, and exciting new preliminary data showing LRP1 regulation of mitochondria numbers in the SC cytoplasm
of myelinated fibers, uniquely positions us to test this hypothesis. In Aim 1, we will examine regulation of SC
mitochondrial heterogeneities and bioenergetics. We propose analyses in whole nerve lysates and isolated
primary SC cultures (mSC) from transgenic mice in which LRP1 is conditionally deleted from SCs (scLRP1-/-).
We plan to challenge mSC metabolism with an innovative LRP1 activator, currently in phase II clinical trials. We
also will test how LRP1 regulated SC mitochondria respond to stress by treatment with a chemotherapy agent
known to induce PPN. In Aim 2, we will identify the mitochondrial proteome by using an unbiased proteomics
screen from neuropathic and naive SCs isolated from scLRP1-/- and scLRP1+/+, respectively. We then build on
the protein blueprint of how conditional deletion of LRP1 in SCs triggers PPN and apply global untargeted
metabolomics to identify key metabolite changes. These studies will reveal entirely new information about
mitochondria dynamics, content, and metabolism of SCs related to PPN.

## Key facts

- **NIH application ID:** 10790951
- **Project number:** 1R21NS135430-01
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** WENDY M. CAMPANA
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $434,500
- **Award type:** 1
- **Project period:** 2023-09-18 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10790951

## Citation

> US National Institutes of Health, RePORTER application 10790951, Regulation of Schwann Cell Mitochondria Homeostasis in Painful Peripheral Neuropathy (1R21NS135430-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10790951. Licensed CC0.

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