Molecular mechanisms regulating mouse valvulogenesis

DESCRIPTION (provided by applicant): Congenital heart diseases (CHDs) are the most common form of birth defects, occurring in as many as 1-5% of newborns, and remain the leading noninfectious cause of infant morbidity and mortality in developed countries. Malformation of valves accounts for up to 30% of CHDs. Despite decades of research, the mechanisms underlying congenital valve diseases remain largely elusive. MicroRNAs (miRNAs) have emerged as promising therapeutic targets/agents for various cardiovascular diseases. While critical roles of miRNAs in regulating cardiomyogenesis have been well established, their activities during valvulogenesis, especially in mammals, have been barely studied. Our current knowledge of miRNA function in developing valves is limited to several publications using zebrafish as the primary model system. The lack of knowledge regarding the roles of miRNAs during mammalian valvulogenesis poses a major barrier to developing diagnostic/therapeutic applications for miRNAs against valve diseases. To directly test whether miRNAs are essential for mammalian valve development, we established a mouse model in which Dicer1 is specifically inactivated in embryonic endocardial cells, which are precursors of valve leaflet cells. Our studies reveal for the first time that the miRNA regulatory machinery in endocardial cells is required for normal valvulogenesis to support survival of neonatal mice. We propose the central hypothesis that miRNAs are essential components of the molecular regulatory network governing normal valvulogenesis in mammals. We will test this hypothesis through the following two Specific Aims. In Aim 1, we will determine the effect of globally blocking miRNA biosynthesis in endocardial cells on valvulogenesis in mice. In Aim 2, we will test the role of miRNA-mediated repression of Ptpn11 in preventing valve hyperplasia. MiRNAs play important roles in numerous biological/pathological processes, and yet their functions during mammalian valvulogenesis have not been examined. Accomplishing these studies will significantly advance our fundamental understanding of the complex molecular/genetic mechanisms regulating mammalian valvulogenesis and provide crucial clues regarding the use of miRNAs for clinical applications against congenital valve diseases.