About
ER stress and epithelial barrier function at the host-environment interface
The intestinal epithelium forms a single cell thick barrier separating us from a myriad of environmental factors, such as the gut microbiome, microbial products, dietary components, and drugs, that affect mucosal barrier function. Maintenance of this barrier is critical for normal physiology, and disruption of the barrier is often associated with human disease.
The unfolded protein response (UPR) is a major cell stress response affecting epithelial barrier function. When the demand for protein folding and secretion exceeds the capacity of the endoplasmic reticulum, misfolded proteins accumulate (i.e. ER stress) and trigger the UPR. The adaptive UPR acts critically to maintain epithelial cell function and homeostasis in the intestine. Dysregulated UPR signaling and unresolved ER stress impairs intestinal stem cell function, alters mucosal barrier host defense, and drives immune cell activation that contribute to intestinal inflammation.
In the Grey Lab, we integrate biophysical, biochemical, cellular, and in vivo approaches to understand fundamental mechanisms regulating epithelial ER stress responses that affect epithelial differentiation, host-microbial interactions, and mucosal barrier function.
Current projects focus on:
- Activation of the ER stress sensor IRE1α by cholera toxin and other metastable proteins
- Function and evolution of the ER stress sensor IRE1β in the epithelial ER stress response and mucin biosynthesis
- Host-microbiota interactions regulating epithelial barrier function in ulcerative colitis
- Impact of genetic variants on protein quality control and ER stress in digestive diseases