Project 172129

In normal human physiology, most cells directly talk to each other through specialized conduits or channels that are built between contacting cells within tissues and organs. The protein molecules used to assemble these specialized cell-cell channels, known as gap junctions, are called connexins. Inherited mutations in the genes that encode these connexins cause severe diseases ranging from deafness to developmental disorders. Most organs in the human body express one particular member of the connexin family called connexin43. Inherited mutations in this connexin lead to a wide range of developmental abnormalities in the hands, feet, facial bone and teeth, and frequently cause chronic disease of the bladder, eyes and nerves. Our group has specialized and published extensively on this disease known as oculodentodigital dysplasia. In the present application, we will use cell and mouse models of oculodentodigital dysplasia to examine how connexin43 mutations lead to moderate or severe disease in some tissues but cause little or no disease in other organs where connexin43 is present. Importantly, we will obtain cells and tissues from patients suffering from this disease to facilitate our studies. Through our multidisciplinary approach of using genetically manipulated cells, mouse models of the disease and human samples from patients, we will provide much needed insight into the basis of how connexin43 mutations cause disease. Finally, our studies should provide important leads into potential therapeutic interventions that may alleviate the severity of the disease in patients suffering from chronic and degenerative problems.