# Molecular mechanisms regulating TLR signaling and inflammation

> **NIH NIH R01** · UNIVERSITY OF TX MD ANDERSON CAN CTR · 2021 · $234,843

## Abstract

PROJECT SUMMARY/ABSTRACT
Toll-like receptor (TLR) signaling plays a crucial role in mediating innate immunity and, when deregulated, also
contributes to the pathogenesis of inflammatory diseases. Better understanding of the molecular mechanisms
regulating TLR signaling and inflammatory responses is highly significant for improving the therapeutic
approaches in the treatment of inflammatory diseases. During the previous funding cycles, the PI’s laboratory
has made seminal discoveries in this area. Moreover, we have generated a large body of innovative preliminary
data that form a solid foundation for this continuation application. In particular, our preliminary studies
demonstrated a crucial role for the protein kinase, TBK1, in controlling TLR signaling and preventing
inflammatory disorders. Although TBK1 is known as a kinase that mediates type I interferon (IFN) induction and
antiviral innate immunity, its in vivo functions have been poorly studied due to the lack of a viable mouse model.
Using newly generated TBK1 conditional knockout (cKO) mice, we have discovered novel functions of TBK1 in
the regulation of immune and inflammatory responses. Our preliminary studies have demonstrated a crucial role
for TBK1 in controlling inflammatory responses by functioning in both innate immune cells and intestinal epithelial
cells (IECs). Myeloid cell-conditional TBK1 KO (Tbk1-MKO) mice are hypersensitive to colitis induction and
spontaneously develop aberrant adipose tissue expansion and inflammation. TBK1 negatively regulates TLR
signaling and TLR-stimulated expression of proinflammatory cytokines in macrophages. We have further
demonstrated that conditional deletion of TBK1 in IECs increases proinflammatory cytokine production and Th17
cell generation in the intestine, sensitizing mice for intestinal tumorigenesis. Based on these innovative findings,
we hypothesize that TBK1 functions in both innate immune cells and IECs to regulate proinflammatory TLR
signaling and inflammatory disorders. The overall objective of this continuation application is to elucidate the
mechanism underlying the anti-inflammatory functions of TBK1. To accomplish this overall objective, we will
perform two specific aims. In Aim 1, we will examine how myeloid cell TBK1 regulates TLR signaling and
inflammation. In Aim 2, we will elucidate the mechanism by which TBK1 functions in IECs to regulate intestinal
immune homeostasis and tumorigenesis. We believe that these proposed studies address novel mechanisms
that regulate TLR signaling and inflammatory responses and will lead to high-impact results that substantially
advance the field.

## Key facts

- **NIH application ID:** 10265710
- **Project number:** 3R01AI057555-18S1
- **Recipient organization:** UNIVERSITY OF TX MD ANDERSON CAN CTR
- **Principal Investigator:** Shao-Cong Sun
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $234,843
- **Award type:** 3
- **Project period:** 2020-08-21 → 2022-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10265710

## Citation

> US National Institutes of Health, RePORTER application 10265710, Molecular mechanisms regulating TLR signaling and inflammation (3R01AI057555-18S1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10265710. Licensed CC0.

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