Septins in Intestinal Epithelial Physiology and Disease

The intestinal epithelium is a single layer of cells that forms our largest interface with the external environment. Its critical roles including secretion of mucus and enzymes, digestion, absorption, coordination of immune system-microbiome crosstalk, and protection against pathogens.

Annually, gastrointestinal (GI) disorders affect ~70 million people, resulting in $135.9 billion in healthcare costs. Several GI disorders, including ulcerations, inflammatory bowel disease (IBD) necrotizing enterocolitis (NEC) and colorectal cancer (CRC), are caused or exacerbated by defects in epithelial barrier integrity.

Epithelial barrier integrity depends on proper regulation of underlying cytoskeletal networks. While the cytoskeletal roles of actin filaments, intermediate filaments, and microtubules in this processes have been extensively explored, an important gap in our knowledge is the role of the newest member of the cytoskeleton: septins, ubiquitously expressed, filament forming proteins. Specific septins are highly expressed in intestinal epithelia, and mutations or changes in their expression levels at the RNA and protein level, are associated with IBD, NEC and CRC.

We interrogate the physiological organization and role of septins in the intestine of live animals using a unique and innovative combination of multi-scale techniques including:

1) intra-vital microscopy procedures to visualize fluorophore-tagged proteins, at super-resolution in the live GI tract
2) knock-in mice expressing fluorophore-tagged septins, and inducible knockout mice, to track manipulate septin expression in GI epithelia
3) in vivo interactome profiling (in collaboration with the Sheynkman Lab) to identify new septin-binding proteins from intact tissue, and dissect their roles in organoid model systems
4) correlation of findings from mouse with human samples, laying the groundwork for translational projects.