# AIBP and regulation of neuropathic pain

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2020 · $443,771

## Abstract

Project Summary
Persistent pain states, arising from inflammatory conditions, such as in arthritis, diabetes, HIV, and
chemotherapy among others, have an extraordinary negative impact on quality of life. A common feature of these
initiating events is the release of damage-associated molecular pattern (DAMP) molecules, which can activate
Toll-like receptor-4 (TLR4). Our previous studies suggest that TLR4 is critical in mediating the transition from
acute to persistent pain. TLR4 as well as other inflammatory receptors localize to lipid raft microdomains on the
plasma membrane. Lipid rafts, enriched with cholesterol and sphingomyelin, facilitate ligand-mediated receptor
dimerization and downstream signaling. Removal of cholesterol from the plasma membrane reduces lipid rafts
and often results in inhibition of receptor function. We have found that the secreted apoA-I binding protein (AIBP)
accelerates cholesterol removal, disrupts lipid rafts, prevents TLR4 dimerization and inhibits microglia
inflammatory responses to LPS. Furthermore, because AIBP binds to TLR4 and its affinity increases when TLR4
is activated by an agonist, we propose that AIBP targets cholesterol removal to lipids rafts harboring activated
TLR4. In our recent work, we have also found that this mechanism is relevant to regulation of neuropathic pain
states. Intrathecal injections of recombinant AIBP prevented LPS-induced tactile allodynia and, remarkably,
reversed established cisplatin-induced allodynia. Based on these findings, we propose that targeted, AIBP-
mediated disruption of lipid rafts and its effects upon TLR4 signaling can be a potential therapeutic strategy in
treating neuropathic pain states. The Specific Aims of this proposal are: (1) to test the hypothesis that AIBP
targets lipid rafts harboring activated TLR4; (2) to test the hypothesis that AIBP reduces glial activation and
neuroinflammation in mouse models of neuropathic pain; and (3) to identify the origin and function of endogenous
AIBP in the spinal cord. To test these hypothesis, we propose experiments, in vivo and in isolated glial cells, to
elucidate the AIBP-TLR4 binding and lipid raft mechanism, and to characterize glial activation and
neuroinflammation states. We will also make AIBP variants with mutated apoA-I or TLR4 binding interfaces to
validate the proposed mechanism. Using our unique AIBP knockout and AIBP flox/flox mice, we will identify the
role of endogenous AIBP in lipid raft regulation and neuroinflammation. In summary, our proposed experiments
will elucidate the mechanisms by which AIBP reduces neuroinflammation and alleviates neuropathic pain. Our
studies may also suggest that raising AIBP levels in the CNS may be a novel therapeutic approach to treat
persistent pain states.

## Key facts

- **NIH application ID:** 9936455
- **Project number:** 5R01NS102432-04
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** Yury Miller
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $443,771
- **Award type:** 5
- **Project period:** 2017-08-15 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9936455

## Citation

> US National Institutes of Health, RePORTER application 9936455, AIBP and regulation of neuropathic pain (5R01NS102432-04). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/9936455. Licensed CC0.

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