- Project 1
- Project 2
- Project 3
Microvillus Inclusion Disease (MVID)
Loss of function mutations in the actin motor, myosin VB (Myo5b) lead to MVID that is manifested by severe diarrhea shortly after birth that leads to death. There is no treatment available for MVID (image1). We are investigating diarrhea in MVID because how mutations in Myo5b lead to diarrhea is not understood. Myo5b regulates delivery of apical cargo to the brush border membrane of epithelial cells. We generated intestinal cellular models of MVID (Image 2, 3) that completely replicate the features of human MVID enterocyte. Studies in our cell models and human MVID tissues indicate that loss of Myo5b leads to alterations in apical traffic of CFTR (Cl/HCO3), NHE3 (Na absorption) and DRA (Cl/HCO3 exchange), the three main apical drivers of intestinal fluid secretion (images 4-6). Surprisingly, we found that Myo5b is selective in regulating apical delivery of ion transporters. CFTR is partially delivered into the membrane, while NHE3 and DRA are not. Our studies indicate that diarrhea results from activation of apically delivered CFTR through defective signaling, inhibition of Na and Cl absorption. We have identified druggable targets for ameliorating MVID diarrhea and working to develop those commercially in collaboration with Yale Office of Coorporate Research. We are generating an intestine specific mouse model of MVID that will be used for continued studies and testing of druggable targets and human intestinal organoid models (image 7) of MVID to continue studies of MVID diarrhea.