# Endocannabinoid Biosynthesis in Inflammation and Pain

> **NIH NIH R01** · UNIVERSITY OF VIRGINIA · 2020 · $388,826

## Abstract

Project Summary
Globally, chronic disorders including cardiovascular disease, diabetes, cancer, and chronic respiratory
disorders represent one of the largest causes of death in industrialized societies. Besides life-threatening
disease, chronic pain currently inflicts millions of American adults and contributes to billions ever year in
medical costs. While complex molecular factors underlie these heterogeneous pathologies, a unifying feature
of numerous chronic disorders is non-resolved inflammation. Thus, new anti-inflammatory targets are needed
to combat the burden of chronic inflammatory disease.
Macrophages accumulate at inflammatory sites to produce lipid and protein inflammatory signaling molecules
that can cause profound changes in physiology including sensitization of peripheral sensory neurons to
promote pathogenesis of chronic pain. We previously discovered that diacylglycerol lipase-beta (DAGLB)
regulates an endocannabinoid-eicosanoid lipid-signaling network critical for activation of proinflammatory
responses in macrophages. Recent preliminary data further support DAGLB-regulated lipid pathways as a safe
and effective point of intervention in mouse models of inflammatory and neuropathic pain that lack
gastrointestinal and overt behavioral side effects. Our proposed studies build on published data from our group
as well as others that point to DAGLB-regulated pathways in macrophages as a novel anti-inflammatory target
for treating chronic inflammation and pain.
Here, we plan to test our central hypothesis that DAGLB-inactivation produces anti-inflammatory effects via
autocrine lipid signaling pathways in macrophages to reduce local inflammatory responses in vivo. We propose
a highly innovative approach that leverages chemical proteomics, mass spectrometry metabolomics, mouse
pain models, and novel small molecule probes that selectivity detect and inactivate DAGLB in vivo. The impact
of our proposed studies include 1) molecular elucidation of crosstalk between lipid and kinase signaling
pathways that explain the anti-inflammatory effects of DAGLB inhibitors, 2) insights into the translational
potential of endocannabinoid biosynthetic pathways in human innate immune biology, and 3) creation of new
drug delivery strategies for targeting macrophage signaling for treating pathological pain. Our long-term goals
are to identify new anti-inflammatory mechanisms and drug delivery strategies for developing targeted anti-
inflammatory drugs suitable for treating chronic disease.

## Key facts

- **NIH application ID:** 9952329
- **Project number:** 5R01DA043571-04
- **Recipient organization:** UNIVERSITY OF VIRGINIA
- **Principal Investigator:** Ku-Lung Hsu
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $388,826
- **Award type:** 5
- **Project period:** 2017-09-15 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9952329

## Citation

> US National Institutes of Health, RePORTER application 9952329, Endocannabinoid Biosynthesis in Inflammation and Pain (5R01DA043571-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9952329. Licensed CC0.

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