Summary
This project aims to understand and therapeutically modulate the intestinal immune system and microbiome to treat colorectal cancer, specifically focusing on RORgt+ regulatory T cells and microbial metabolites.
Treating colon cancer by regulating intestinal immunity through microbial metabolism
US · IL
NIH
grant
open
#nih-5R01CA259634-05
What they want
The project addresses three key gaps: 1) basic knowledge of the diet-microbe-metabolite-immune signaling network, 2) safe and effective means for localized metabolite delivery, and 3) validated targets for defined therapeutic contexts. Aim 1 will dissect the mechanism of a previously unknown microbiome-metabolite-immune pathway by which the microbiome and dietary tryptophan regulate intestinal RORgt+ Treg populations. Aim 2 will engineer a probiotic strain of E coli as a general platform for localized delivery of therapeutic metabolites, initially to boost RORgt+ Tregs by overproducing butyrate. Aim 3 will evaluate the efficacy of elevating RORgt+ Tregs (via dietary butyrate) on key outcomes for sporadic vs colitis-associated CRC in vivo.
Deliverables
- Basic knowledge of the diet-microbe-metabolite-immune signaling network
- Safe and effective means for localized metabolite delivery
- Validated targets for defined therapeutic contexts
- Engineered probiotic strain of E coli for therapeutic metabolite delivery
- Evaluation of efficacy of elevating RORgt+ Tregs on sporadic vs colitis-associated CRC in vivo
- Deeper understanding of metabolic immunoregulation
Technical requirements
- Focus on RORgt+ regulatory T cells (RORgt+ Tregs)
- Dissection of microbiome-metabolite-immune pathway involving dietary tryptophan
- Engineering of a probiotic strain of E coli
- Localized delivery of therapeutic metabolites (e.g., butyrate)
- In vivo evaluation in sporadic vs colitis-associated CRC models
