The unifying hypothesis to be tested in this proposal is that the compartmentalized regulation mediated by Guanylate Cyclase-C (GC-C), Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) and Multiple Drug-associated Protein-4 (MRP4) macromolecular complexes at or near the plasma membrane of gut epithelial cells regulates cGMP mediated secretory diarrhea. We will test this hypothesis using transgenic mice model (in vivo studies) and patient derived intestinal stem cells derived from crypts (enteroids) to study fluid secretion in vitro. The proposed studies are highly significant because (i) it addresses the pathologies of several deadly human diseases by utilizing models from humans and mice; (ii) it has clinical relevance and implications; (iii) it is a multidisciplinary project covers basic biomedical studies, assay developments, and uses personalized human stem cell cultures.
In this grant proposal, we will address a novel mechanism of how protein-protein interactions can contribute to the progression of Travelers diarrhea (TD). We hypothesize that compartmentalized regulation mediated by Guanylate Cyclase-C (GC-C), Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) and Multiple Drug-associated Protein-4 (MRP4) macromolecular complexes at or near the plasma membrane of gut epithelial cells regulates cGMP (cyclic guanosine monophosphate) mediated secretory diarrhea. By targeting this macromolecular complex, we may find ways to control fluid secretion and thereby control or cure the disease.
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