Current Projects:

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.

Chronic constipation is a major and increasingly common problem among children and adults. We work with pharmaceutical companies to examine how drugs such as linaclotide (Linzess, Ironwood Inc.) activate CFTR traffic in the intestine to increase fluid secretion and improve obstructive symptoms of chronic constipation. Linzess is approved for chronic idiopathic constipation (CIC) and IBS-C in adults. We recently showed that Linzess improves constipation by increasing CFTR mediated intestinal fluidity by activating traffic into the brush border membrane. Physiological Reports, 5 (11), 2017

Obstructive disease of the intestine is a hallmark of cystic fibrosis (CF) and results from defective CFTR-mediated Cl- and HCO3- secretion. Infants with CF display meconium ileus while older children and adults present with recurrent bouts of constipation and distal intestinal obstruction (DIOS). Meconium ileus, DIOS and constipation are frequently observed in patients possessing the common CFTR DF508 mutation, leading to frequent hospital admissions and occasional surgery.

Although FDA approved drugs aimed at correcting the cellular defects in CF have shown some benefit in improving BMI and growth with Orkambi, a combination of ivacaftor and lumacaftor, patients continue to require daily laxatives to help obstructive intestinal disease. We are currently exploring alternative cheaper FDA approved drugs to examine whether they can be useful in activating and rescue DF508 traffic and function in the intestine.