# Characterizing the negative signaling in dendritic cells and macrophages to attenuate inflammation and bone destruction in Rheumatoid arthritis

> **NIH NIH R01** · UNIVERSITY OF ALABAMA AT BIRMINGHAM · 2021 · $22,869

## Abstract

The goal of this proposal is to understand the mechanisms underlying how negative endogenous signaling
reduces chronic inflammation in rheumatoid arthritis (RA), which can provide novel therapeutic targets for
diseases related to inflammation and tissue destruction. Current therapies for RA have serious negative effects
on the patients’ immune system, and can cause malignancies, pneumonia, and tuberculosis. Positive regulators
of inflammation in RA (such as NF-κB) have been well characterized, however, the negative endogenous
regulators of RA-induced inflammation and bone destruction, especially in macrophages and dendritic cells in
RA pathological condition remain elusive. The proposed study will characterize the negative endogenous
regulators of differentiation and activity in macrophages and dendritic cells (DCs) that attenuate RA-induced
inflammation and tissue destruction. We noted that Gα13 deficiency in macrophages or dendritic cells
aggravated inflammation in mouse RA model. AAV mediated overexpression of local Gna13 constitutively
active form (Gna13CA) not only significantly reduced bone destruction, but also dramatically inhibited
inflammation in RA, indicating that Gna13CA could protect against inflammation in a mouse model of RA. Our
RNA sequencing (RNA-seq) analysis showed that Gα13 may negatively regulate macrophage and DC
differentiation and activation and ChIP sequencing (ChIP-seq) analysis showed the enrichment of NF-κB motif
site binding on the genome-wide promoters of the genes related to inflammation in Gα13 deficient macrophages
with TNFα or LPS stimulations. Our preliminary data showed that Gα13 deficiency promotes Akt activity, STAT3
phosphorylation and NF-κB signaling pathway activation in dendritic cells and macrophages. Based on
our preliminary studies, we hypothesize that Gα13 is a master negative regulator that attenuates inflammation
and bone destruction associated with rheumatoid arthritis through the Gα13/RhoA/AKT/IKK/NF-κB pathway in
macrophages and dendritic cells. Three specific aims are proposed to test our hypothesis. In Aim 1, we will
determine the role of Gα13 in inflammation and bone destruction in rheumatoid arthritis (RA) by characterizing
the phenotypes and pathomechanism of conditional knockout (CKO) mouse models via loss-of-function
approach in RA. In Aim 2, we will define the roles and therapeutic effects of Gα13CA in inflammation and bone
destruction in RA by characterizing the phenotypes and pathomechanism of conditional transgenic
overexpression (OE) mouse models via gain-of-function approach in RA. We will characterize the molecular
mechanism by which Gα13 regulates inflammation and bone destruction in RA through Gα13/
RhoA/AKT/IKK/NF-κB signaling, STAT3 signaling, and TLRs signaling pathways in macrophages and dendritic
cells in Aim 3. The proposed study will provide important insights into the negative regulation of the cells of the
immune system to effectively target inflammation and bone destru...

## Key facts

- **NIH application ID:** 10107765
- **Project number:** 5R01AR074954-02
- **Recipient organization:** UNIVERSITY OF ALABAMA AT BIRMINGHAM
- **Principal Investigator:** YI-PING LI
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $22,869
- **Award type:** 5
- **Project period:** 2020-02-15 → 2021-04-06

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10107765

## Citation

> US National Institutes of Health, RePORTER application 10107765, Characterizing the negative signaling in dendritic cells and macrophages to attenuate inflammation and bone destruction in Rheumatoid arthritis (5R01AR074954-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10107765. Licensed CC0.

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