# Resolution of Inflammation by the SIX-family Transcription Factors

> **NIH NIH R01** · UT SOUTHWESTERN MEDICAL CENTER · 2022 · $410,000

## Abstract

Project Summary
The present study focuses on our discovery that developmentally silenced SIX-family transcription
factors are reactivated by TNF-family cytokines and potently suppress gene expression programs
induced by non-canonical NF-kB. By first characterizing the human cytokines and pathogen
associated molecular patterns (PAMPs) that induce Six1 and Six2 protein expression and by then
investigating the molecular components required for their reactivation (Aim 1), these studies will
reveal a new pathway for non-canonical NF-kB regulation in the mammalian immune system. Second,
we will determine how Six-proteins inhibit inflammatory gene expression programs through promoter
proximal mechanisms (Aim 2). Physiological significance of inflammatory resolution by Six-proteins
while be investigated in mammalian model organisms using three complementary mouse models of
Six1 protein function (Aim 3). Insights gleaned from these studies will explain how non-canonical NF-
kB is regulated at gene promoters and will also reveal co-repressor complexes that play important
roles in the inflammatory response to microbial pathogens. Developing new drugs that interfere with
the ability of SIX proteins to regulate non-canonical NF-kB during microbial infection would be an
innovative approach to combat human disease associated with NF-kB signaling dysfunction including
chronic inflammation. Therefore, by revealing molecular details of SIX-protein function in the
mammalian immune system, from biochemistry to mouse models of infection, we will uncover sites of
potential weakness that may be exploited for therapeutic intervention. Importantly, these studies will
also provide new insights into the pathogenic mechanisms of an important infectious disease-causing
agent and also into the biology of the human inflammatory response.

## Key facts

- **NIH application ID:** 10328259
- **Project number:** 5R01AI150982-03
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** Neal Mathew Alto
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $410,000
- **Award type:** 5
- **Project period:** 2020-02-21 → 2025-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10328259

## Citation

> US National Institutes of Health, RePORTER application 10328259, Resolution of Inflammation by the SIX-family Transcription Factors (5R01AI150982-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10328259. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*