# The Role of the Smcr8-Wdr41-C9orf72 (SWC) Complex in the Maintenance of Intestinal Homeostasis

> **NIH NIH R01** · UT SOUTHWESTERN MEDICAL CENTER · 2021 · $441,637

## Abstract

PROJECT SUMMARY/ABSTRACT
The balance of the gastrointestinal tract and return to a state of equilibrium after times of stress (infectious,
chemical or otherwise) is a critical determinant in regulating many human intestinal disorders including those of
autoimmune and infectious origins. Perhaps the best studied genetic intestinal disorder is inflammatory bowel
disease (IBD), however, the exact etiology of IBD is not fully understood. In order to better understand intestinal
immune homeostasis, we carried out a forward genetic screen to unbiasedly identify these essential genes with
non-redundant functions. To date, we have used this method to examine 49,690 mice, which serve as a reservoir
for 104,845 mutant alleles in the coding or splicing of 19,368 genes. Susceptibility to experimental colitis results
from mutations in genes in a number of broad functional categories, including classical immune genes, growth
factors, and extracellular matrix proteins as well as from mutations in genes with less expected functions such
as vesicular trafficking and metabolism. We have chosen to examine a subset of genes (Smcr8 and Wdr41) that
cause a striking phenotype and exist along with C9orf72 in the same macromolecular complex linked to vesicular
transport. The Smcr8-Wdr41-C9orf72 (SWC) complex is a tripartite guanine nucleotide exchange factor that
stands at the intersection of multiple human disease pathways, inflammatory signaling, autophagy, and
lysosomal transport. In this proposal, we will examine the components that mediate the cellular and molecular
dysfunction in SWC complex deficiency and the resulting pathology in three Specific Aims: (1) To examine
cellular components requiring the SWC complex for regulating intestinal and peripheral inflammation. (2) To
understand the molecular mechanism, signaling pathways and in vivo consequences of endosomal TLR
dysregulation in SWC deficiency. (3) To examine the mechanism by which the SWC complex regulates
phagolysosomal maturation. The aims in this proposal will help elucidate the mechanisms underlying the
crosstalk between lysosomal maturation to inflammatory signaling and thus expand our knowledge of the
mechanisms underlying gastrointestinal disorders such as IBD.

## Key facts

- **NIH application ID:** 10173759
- **Project number:** 5R01DK119360-02
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** Emre Erol Turer
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $441,637
- **Award type:** 5
- **Project period:** 2020-06-01 → 2024-02-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10173759

## Citation

> US National Institutes of Health, RePORTER application 10173759, The Role of the Smcr8-Wdr41-C9orf72 (SWC) Complex in the Maintenance of Intestinal Homeostasis (5R01DK119360-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10173759. Licensed CC0.

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