# Role of SCGN in Intestinal Immune Homeostasis

> **NIH NIH K08** · UT SOUTHWESTERN MEDICAL CENTER · 2022 · $167,400

## Abstract

PROJECT SUMMARY
I am an Assistant Professor in the Division of Pediatric Gastroenterology, Hepatology and Nutrition at The
University of Texas Southwestern Medical Center. My long-term career goal is to become an independent
researcher investigating genetic drivers of inflammatory bowel disease. Inflammatory bowel disease (IBD) is
thought to result from critical environmental exposures in genetically susceptible individuals. However, much of
the genetic susceptibility remains unaccounted for. In this regard, mechanistic studies of defined genetic variants
associated with IBD can help us fill these critical gaps and may provide novel therapeutic targets.
I have previously reported the identification of a mutation in the SCGN gene causing early-onset ulcerative colitis.
SCGN encodes secretagogin, a calcium sensor exclusively expressed in neuroendocrine lineages, including
enteroendocrine cells and gut neurons and participates in SNARE mediated secretion. The mutation identified
in humans leads to abnormal SCGN-SNAP-25 membranous localization resulting in impaired hormone secretion,
mimicking complete SCGN loss. Scgn deficiency in mice results in enhanced DSS colitis susceptibility. Our data
suggests that the enteric nervous system might be responsible for the observed colitic phenotype. Subsequent
preliminary data indicates that Scgn loss in mice results in hyperactivation of intestinal epithelial type I interferon
response.
The central hypothesis of this proposal is that neuroendocrine dysfunction resulting from SCGN deficiency plays
a role in IBD pathogenesis through disruption of innate immune responses, specifically Type I interferon
activation in the epithelium. The project’s overall goal is to study the role of SCGN in intestinal inflammation
through the following specific aims:
Aim 1 – To define the neuroendocrine lineage cells responsible for SCGN-dependent intestinal inflammation.
Aim 2 – Determine the contribution of type I interferon signaling in SCGN-associated colitis susceptibility.
Aim 3 – To identify SCGN-dependent immunoregulatory factors
To carry out the work proposed in this mentored Career Development Award, I have developed a career
development plan that takes advantage of the scientific environment at UTSW, with a specific focus on
development of skills related to in-vivo models of intestinal inflammation and next-generation sequencing data
analysis. I have brought together a mentorship/advisory committee composed of experienced clinical and basic
science researchers with a focus on human genetics, intestinal inflammation and IBD. My main mentor, Dr. Ezra
Burstein, leads this team. In summary, the information gained from the studies proposed here will shed light on
the immune-regulatory role a group of cells not commonly thought to be key mediators of inflammation, have in
the intestine, with the ultimate promise of propelling me towards independence.

## Key facts

- **NIH application ID:** 10364664
- **Project number:** 5K08DK127197-02
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** Luis Sifuentes-Dominguez
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $167,400
- **Award type:** 5
- **Project period:** 2021-03-10 → 2025-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10364664

## Citation

> US National Institutes of Health, RePORTER application 10364664, Role of SCGN in Intestinal Immune Homeostasis (5K08DK127197-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10364664. Licensed CC0.

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