# Mitochondrial Mechanisms Promoting Innate and Intestinal Immunity

> **NIH DK R01** · YALE UNIVERSITY · 2026 · $497,895

## Abstract

Project Summary/Abstract: Inflammatory bowel disease (IBD) is largely characterized by dysregulated
cytokines and antimicrobial responses. Innate mechanisms are the initiating drives of host responses to
microbes and the resulting cytokine and antimicrobial responses need to be carefully balanced. Mitochondrial
pathways play a key role in mediating these innate responses and a dysregulation in mitochondrial
mechanisms has been increasingly recognized to play a role in IBD. The focus on the mitochondrial
dysregulation in IBD has been predominantly in epithelial cells. However, mitochondria contribute to innate
immune outcomes through a variety of mechanisms, including metabolic pathways, reactive oxygen species,
communication with the endoplasmic reticulum (ER), and mitochondrial DNA (mtDNA) release. Of the >240
IBD-associated loci a number of genes within these loci modulate host innate responses and mitochondrial
function through both direct and indirect mechanisms. As such, upon encounter of human macrophages with
microbial products, we have found IBD-associated genes that regulate glycolysis and in turn macrophage
polarization, the mitochondrial respiratory chain and mtROS, and ER stress. We further find that upon human
macrophage stimulation by a range of pattern recognition receptor (PRR) ligands, release of mtDNA is
dramatically increased along with activation of the cGAS- STING pathway. The cGAS-STING pathway then
serves to promote responses across the many PRRs. We have preliminary data that at least one IBD-
associated gene which partially localizes to the mitochondria, LACC1, modulates PRR-induced activation of
the cGAS-STING pathway, and in turn, downstream PRR-initiated downstream outcomes. We hypothesize
that the cGAS-STING pathway amplifies responses across a broad range of PRRs through a variety of
intracellular mechanisms, that the threshold of this regulation is important in susceptibility to intestinal
inflammation and might be therapeutically targ

## Key facts

- **NIH application ID:** 11290324
- **Project number:** 5R01DK135587-04
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** CLARA  ABRAHAM
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** DK
- **Fiscal year:** 2026
- **Award amount:** $497,895
- **Award type:** 5
- **Project period:** 2023-03-15T00:00:00 → 2027-01-31T00:00:00

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11290324

## Citation

> US National Institutes of Health, RePORTER application 11290324, Mitochondrial Mechanisms Promoting Innate and Intestinal Immunity (5R01DK135587-04). Retrieved via AI Analytics 2026-05-20 from https://api.ai-analytics.org/grant/nih/11290324. Licensed CC0.

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