Based on genetic and cellular discoveries made in the PI lab and his collaborators, this proposal focuses on novel mechanisms that are critical for formation of heart valves. Data presented in the proposal show that mutations in the DZIP1 gene cause a very common heart valve disease (i.e., mitral valve prolapse) and can be caused by errors in how valve tissue forms during development. These discoveries have led to a novel concept that cilia are involved in valve development. As such, our proposal evaluates how cilia form during development and how DZIP1 functions to regulate both ciliogenesis and/or ?-catenin activities during development. Our studies will provide unique opportunities to answer questions about heart-valve diseases that heretofore have been impossible to answer using even state-of-the-art biological and genetic approaches. Valvular heart disease is a serious clinical problem, affecting 5-7% of the human population. Its complications include congestive heart failure, endocarditis, atrial arrhythmias, and sudden death. There are no known non- surgical cures for this group of disease. The proposed work capitalizes on previously unrecognized genetic data collected from heart valve disease patients; studies in the mouse show that this class of genes is an important and previously unrecognized contributor to valve structural development and disease pathogenesis. The uncovering of this particular disease gene and the processes it regulates holds great potential for future remedial or therapeutic insight towards regeneration or formation of mechanically stable valve tissue that will be beneficial to valvular heart disease patients.
Little is known regarding the etiology of mitral valve prolapse (MVP), one of the most common diseases, affecting 1 in 40 individuals. Uncovering the genetic causes for this disease will provide key insight into mechanisms that contribute to valve development and allow us to study why MVP happens. Based on our genetic, developmental and molecular discoveries, our goal for this proposal is to examine new mechanisms for valvular development and their link to the pathogenesis of cardiac valve diseases.