With a long-term goal of designing and executing studies in epithelial biology of the intestine, I seek support in my career development through this Mentored Clinical Scientist Research Career Development Award (K08). With the recent completion of my Pediatric Gastroenterology and Hepatology fellowship and transition to faculty, this career development award will provide me with the necessary components for an independent physician-scientist career path at the interface between pediatric gastroenterology and epithelial biology via the following: (1) formal education in molecular cell biology, study design and laboratory research (CREST) including advanced coursework in cell biology, (2) research training in epithelial cell biology including in vitro techniques, immunohistochemistry, epithelial integrity measures within Dr. Barrett's laboratory, (3) clinical precepting and (4) a structured plan for publications, presentations, and mentoring oversight. This proposal is feasible because of the sound career development and research plans as well as the strong support from my mentors, advisory committee, and the Department of Pediatrics at UCSD. Congenital Tufting Enteropathy (CTE) is a genetic disorder characterized by severe chronic watery diarrhea in infancy. The villous atrophy associated with CTE leads to dependency on parenteral nutrition and significant morbidity and mortality with limited treatment options. Using a systematic genetic mapping approach, we were able to identify mutations in the gene that codes for Epithelial Cell Adhesion Molecule (EpCAM). The goal of this project is to elucidate the underlying disease mechanisms in CTE and EpCAM's role in the intestine using in vitro models of intestinal epithelial cells with focus on cellular, intracellular and tissue changes. We hypothesize that epithelial cell adhesion molecule (EpCAM) mutations cause aberrations in cell biology leading to the characteristic intestinal pathology and barrier disruptions in the intestinal epithelium resulting in the clinical manifestations of Congenital Tufting Enteropathy. Using in vitro models we will focus on (1) investigation of the effect of mutation or knockdown of EpCAM on epithelial cell size, morphology and intercellular interactions, (2) characterization of the protein-protein interactions of normal and mutant EpCAM in epithelial cells, and (3) assessment of the effect of mutation or absence of EpCAM expression on epithelial cell migration, reassembly, and intestinal permeability. This grant provides a unique opportunity to study the mechanisms of intestinal cell adhesion, gastrointestinal absorption, and secretory diarrhea from a molecular perspective. The studies we propose may yield novel insights into the role of EpCAM in the intestinal epithelium, under normal and pathological conditions, and ultimately contribute to the development of new treatments for CTE and other diarrheal diseases.
We recently discovered evidence linking EpCAM mutations to patients with Congenital Tufting Enteropathy (CTE), a severe congenital diarrheal disorder. In this proposal we aim to elucidate the importance of EpCAM, a molecule found throughout the gastrointestinal tract. Discerning EpCAM's role should help us understand CTE, other diarrheal diseases and more about the lining of the normal digestive system.
|Kozan, Philip A; McGeough, Matthew D; Peña, Carla A et al. (2015) Mutation of EpCAM leads to intestinal barrier and ion transport dysfunction. J Mol Med (Berl) 93:535-45|
|Mueller, James L; McGeough, Matthew D; Peña, Carla A et al. (2014) Functional consequences of EpCam mutation in mice and men. Am J Physiol Gastrointest Liver Physiol 306:G278-88|
|Schnell, Ulrike; Kuipers, Jeroen; Mueller, James L et al. (2013) Absence of cell-surface EpCAM in congenital tufting enteropathy. Hum Mol Genet 22:2566-71|
|Sivagnanam, Mamata; Mueller, James L; Szigeti, Reka et al. (2012) Transcriptional Read-Through Induction Treatment Trial in Intestinal Failure Induced by an EpCAM Nonsense Mutation. Case Rep Med 2012:173195|