# Endoplasmic Reticulum Stress Controls Innate Lymphoid Cells in Intestinal Inflammation

> **NIH NIH K08** · WASHINGTON UNIVERSITY · 2024 · $168,084

## Abstract

PROJECT SUMMARY/ABSTRACT
 This application proposes a five-year research career development program focused on innate lymphoid
cells in the pathogenesis and individualized management of inflammatory bowel disease. The applicant, Siyan
Cao, M.D., Ph.D., is an Instructor of Medicine at the Division of Gastroenterology at Washington University
School of Medicine. Since completing gastroenterology fellowship, Dr. Cao has been working in the laboratory
of Dr. Marco Colonna, where he discovered a novel role of endoplasmic reticulum stress in innate lymphoid cells.
This proposal is an extension of the candidate’s previous work demonstrating IRE1α-XBP1-medicated stress
pathway controls the activation of innate lymphoid cells in murine colitis and patients with inflammatory bowel
disease. The proposed experiments will incorporate innate and mucosal immunology expertise from the
candidate’s mentor, Dr. Marco Colonna, immune cell-epithelial cell interaction and microbiome experience from
the candidate’s co-mentor, Dr. Rodney Newberry, RNA modification and degradation expertise from the
candidate’s co-mentor, Dr. Nicholas Davidson, as well as expertise on intestinal organoids, tissue fibrosis, and
translational/clinical studies from the candidate’s Research Advisory Committee members, Drs. Matthew Ciorba,
Andreas Herrlich, and Parakkal Deepak. Together, the candidate will be uniquely positioned to acquire the
knowledge and skill sets necessary to develop an independent research program investigating how cellular
stress response orchestrates innate immunity in gut inflammation and open avenues for novel management in
inflammatory bowel disease.
 Innate lymphoid cells reside on the mucosal surface and control tissue homeostasis. IRE1α-XBP1 is the
regulatory hub of endoplasmic reticulum stress and implicated in inflammatory bowel disease in genome-wide
association studies. IRE1α is highly expressed in innate lymphoid cells, although its role in those cells remains
unknown. My studies have established that IRE1α-XBP1 controls the activation of innate lymphoid cells in both
mouse colitis models and human inflammatory bowel disease. Using a comprehensive approach involving
lymphocyte-organoid co-culture, genetic mouse models, and longitudinal patient cohorts, this proposal intends
to elucidate the mechanistic role of IRE1α-XBP1 in innate lymphoid cells in intestinal inflammation, and how
those pathways may become novel response biomarkers in inflammatory bowel disease. Ultimately, with the
mentorship provided by Drs. Colonna, Newberry, Davidson, and the other Research Advisory Committee
members, the knowledge and technical skills derived from the proposed experiments, and completion of the
outlined career development plan, Dr. Cao will be well-prepared to establish an independent research program
and is expected to be highly competitive for R01 funding.

## Key facts

- **NIH application ID:** 10949686
- **Project number:** 1K08DK140612-01
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Siyan Cao
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $168,084
- **Award type:** 1
- **Project period:** 2024-09-01 → 2029-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10949686

## Citation

> US National Institutes of Health, RePORTER application 10949686, Endoplasmic Reticulum Stress Controls Innate Lymphoid Cells in Intestinal Inflammation (1K08DK140612-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10949686. Licensed CC0.

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