# Genetic dissection of neural pathways that modulate systemic inflammation

> **NIH NIH R01** · DANA-FARBER CANCER INST · 2021 · $445,000

## Abstract

Project Summary
The broad goal of this research is to improve (i) the potency, (ii) safety, and (iii) the credibility of nerve
stimulation as a treatment for sepsis by defining the functional neural circuitry. In the USA, among 1-3 million
patients suffering sepsis each year, 15-30% will die and many of the survivors will suffer organ damage.
Conventional therapeutic regimens are thus far inadequate. Against this backdrop, nerve stimulations such as
non-invasive electroacupuncture stimulation (ES) at specific acupoints can attenuate systemic inflammation
associated with sepsis and promote survival of laboratory animals. To date, one dominant view is that ES
drives vagal nerve-dependent anti-inflammatory pathways, involving activation of sympathetic cells and
subsequent modulation of pro-inflammatory cytokine release from immune cells. However, there are two
important unresolved issues that must be addressed in order to realize the full potential of ES as a therapeutic
modality for sepsis. First, the roles of sympathetic neurons are still ill-defined. Noradrenaline (NA), one of
transmitters released from sympathetic cells, has long been proposed to suppress systemic inflammation, via
activation of β2 adrenergic receptors. However, NA can also promote inflammation via activation of α2
adrenergic receptors, and this pro-inflammatory signaling can be sensitized following macrophage pre-
exposure to bacteria-derived endotoxins such as the lipopolysaccharide (LPS). Accordingly, it remains
unknown i) if ES could be counterindicated when sepsis has progressed to certain stages, and ii) if a strategy
to maximize the anti-inflammatory over the pro-inflammatory activity is pivotal for ES to treat severe sepsis.
Second, it has been long known that ES can drive vagal parasympathetic reflexes only in specific acupoints,
but the underlying neural basis is entirely unknown. Because of unknown identities and anatomical
distributions of somatosensory neurons driving vagal reflexes, it becomes difficult to optimize stimulation
parameters to activate this anti-inflammation pathway. To address these unresolved issues, we have
developed innovative genetic tools to ablate, silence or activate molecularly defined sympathetic and
somatosensory neurons. Built upon strong preliminary results, we postulate i) that sensory neurons marked by
the expression of the G protein-coupled receptor Prokr2 are required to for low electric intensity ES (0.5 mA) to
drive vagal reflexes, and ii) that noradrenergic sympathetic neurons marked by the expression of the
neuropeptide NPY, which can be activated by high intensity ES (3 mA), may suppress and promote
inflammation, dependent on ES delivered before or after sepsis manifestation. A series of predictions from
these hypotheses will be tested. In the fullness of time, the studies outlined in this application will enable us to
illustrate distinct neuronal pathways that can dynamically modulate sepsis-associated systemic inflammation,
and...

## Key facts

- **NIH application ID:** 10251945
- **Project number:** 5R01AT010629-03
- **Recipient organization:** DANA-FARBER CANCER INST
- **Principal Investigator:** QIUFU MA
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $445,000
- **Award type:** 5
- **Project period:** 2019-09-16 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10251945

## Citation

> US National Institutes of Health, RePORTER application 10251945, Genetic dissection of neural pathways that modulate systemic inflammation (5R01AT010629-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10251945. Licensed CC0.

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