Inflammatory Bowel Disease has a striking relevance today, as we are facing a steep rise of incidence over the past decades, especially in Western and Eastern Asian countries. The pathomechanisms however still need to be further investigated. It is known that a complex genetic risk architecture hand in hand with environmental/microbial factors contribute to disease onset and perpetuation. The intestinal epithelium displays the barrier interface between gut microbial communities and mucosal tissue and is critical in orchestrating immune signals. Key cellular processes in this context are ER stress resolution and autophagy. ER stress resolution is partly done by selective ER phagy, which requires ER- resident receptors as the receptor family with sequence similarity 134 member B (Fam 134b), also called reticulophagy regulator 1 (RETREG1). So far loss of this receptor is mainly known for leading to neurodegeneration and neuronal disorders such as hereditary motor sensory neuropathy type 1 (HMSN I) (Khaminets et al., Nature 2015), but preliminary data shows also a link to inflammation in the intestinal system.
Our goal is to hypothesize a critical function in orchestrating immune signals by the ER phagy receptor Fam 134b. We aim to study the interplay with microbial factors and metabolites as preliminary data hint towards profound regulation of ER phagy receptor expression by short-chain fatty acids like butyrate.
We set out to investigate the role of Fam134b in epithelial homeostasis using genetic in vivo models (conditional knockout mice), organoid models and CRISPR/Cas9-modified cellular systems.