# NOVEL STRATEGIES FOR INTERVENTION OF INFLAMMATORY DISEASES AND CANCER

> **NIH NIH R01** · UNIVERSITY OF SOUTHERN CALIFORNIA · 2020 · $313,500

## Abstract

PROJECT SUMMARY
Colorectal cancer (CRC), the third leading cause of cancer deaths in the United States, is a challenging disease
involving complex interplay among immune cells, cytokine-mediated pathways and gut microbiota – leading to
inflammation, disruption of the epithelial tissue barrier, acute colitis and CRC development. Thus, mechanistic
studies are urgently needed to clarify the interactions and consequences of these key variables, enabling the
identification of novel targets for therapeutic intervention. In the course of studies funded by our previous award
(R01 CA101795), we identified TAK1 (TGF-beta-activated kinase 1) as a negative regulator of NF-κB signaling
in neutrophils and found that its specific deletion in the myeloid lineage (Tak1ΔM/ΔM) leads to increased
proinflammatory cytokines (IL-1β, IL-6, and TNF-α) and greater sensitivity to LPS-induced septic shock.
 Unexpectedly, Tak1ΔM/ΔM mice were completely resistant to chemically induced acute colitis and CRC
development. This phenotype was associated with a marked accumulation of Th17 and ILC3 cells in the intestinal
lamina propria and alterations of the gut microbiota composition. Further studies showed significant suppression
of chemokine expression in colon epithelial cells and of immune cell trafficking into colon tissues. These intriguing
new findings led us to hypothesize that specific gut microbiota, Th17 and ILC3 cells and their cytokines (IL-17
and IL-22) play critical roles in regulating resistance to colitis and inflammation-related CRC through the
suppression of chemokine expression by colon epithelial cells. Key predictions of this hypothesis will be tested
in three specific research aims, all relying on the Tak1ΔM/ΔM model of suppressed colitis and CRC tumorigenesis.
Aim 1 seeks to identify specific strains of microbiota that contribute to the accumulation of Th17 and ILC3 cells
and thus to resistance to experimental colitis and CRC. Aim 2 will define the functions of Th17 and ILC3 cells
(and of their cytokines) in promoting resistance to chemically induced colitis and CRC, while Aim 3 will test the
hypothesis that Th17/ILC3-derived cytokines inhibit the expression of chemokines by colon epithelial cells, thus
blocking subsequent immune cell infiltration of the epithelial layer and ultimately the induction of malignant
changes in the colon.
 Upon successful completion of this work, we expect to have a much-improved understanding of the
inflammatory processes that drive the development of ulcerative colitis and CRC, and thus of potential
vulnerabilities in this network that could be targeted for the prevention or treatment of these disorders.

## Key facts

- **NIH application ID:** 10077119
- **Project number:** 7R01CA101795-13
- **Recipient organization:** UNIVERSITY OF SOUTHERN CALIFORNIA
- **Principal Investigator:** Rongfu Wang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $313,500
- **Award type:** 7
- **Project period:** 2004-07-01 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10077119

## Citation

> US National Institutes of Health, RePORTER application 10077119, NOVEL STRATEGIES FOR INTERVENTION OF INFLAMMATORY DISEASES AND CANCER (7R01CA101795-13). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10077119. Licensed CC0.

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