Vanderbilt Institute of Chemical Biology

The Goldenring laboratory in the Epithelial Biology Center studies aspects of epithelial biology and pathobiology. Present investigations focus on two different areas. First, the laboratory has been dedicated to the analysis of apical vesicle trafficking and apical membrane recycling for over 20 years. Investigations focus on the regulation of apical membrane trafficking in normal intestinal enterocytes as well as in enterocytes from mice and humans with deficits in key trafficking proteins (e.g. MYO5B in Microvillus Inclusion Disease) or regulators (e.g. DGAT1) that lead to congenital diarrheal disease. The laboratory uses live cell, confocal and SIM imaging to characterize apical vesicle trafficking in whole tissue as well as in cultured enteroids from mouse, pig and human sources. The goal in these studies is to understand the complexity of trafficking pathways that deliver requisite pumps and channels to the apical membrane and to devise therapeutic strategies to circumvent blockade of apical trafficking in congenital diarrhea syndromes.

The second area of interest in the lab is the origin of pre-cancerous lesions in the stomach. The lab has developed paradigm shifting data over the past decade that has led to the conclusion that pre-cancerous metaplasia does not arise from altered resident stem cells in the stomach, but rather develops from transdifferentiation of protein-secreting chief cells into metaplastic mucous-secreting cells. Studies in the laboratory focus on how immune cell populations (M2-macropahges and IL-C2 cells) regulate the induction of metaplasia and its progression to more aggressive and proliferative pre-cancerous lesions.

Other studies are seeking to identify the characteristics of pre-cancerous stem cell populations using metaplastic and dysplastic organoid lines isolated from both mouse models and human patients. These studies are coordinated with ongoing studies of the utility of MEK inhibitor treatment to reverse metaplasia and allow re-establishment of normal gastric lineages. The work coordinates in vitro studies with initiation of a human trial of MEK inhibitor treatment for reduction of risk of gastric cancer in those with extensive metaplasia. These gastric carcinogenesis studies utilize organoid cultures and live cell imaging, immune cell characterization by multiplex imaging techniques, co-culture studies of stromal cell influence on metaplastic and dysplastic cells, mouse models for targeted analysis of metaplasia, and human and mouse stem cell analyses using single cell RNA sequencing.

All of the work is funded by multiple federal grants (NIH, VA, DOD) and a Cancer UK Grand Challenge grant.