This project will provide the applicant with graduate training in the field of cardiovascular developmental genetics. Among other career development activities, an independent research project will be pursued to further an understanding of how intercellular signals regulate heart valve development. Mammalian heart valve development is directed by a series of coordinated steps by which primitive embryonic heart structures, called endocardial cushions, mature into complex, elongated, and stratified valves. These steps require cell signals to sequentially direct cell differentiation, proliferation, and tissue morphogenesis. The slightest disruption of these signals can yield serious congenital heart defects due to the finely tuned molecular mechanisms underlying valve development. What are these signals and when and where are they functioning? The applicant's preliminary data suggest that Wnt signals have key, unresolved roles at multiple stages of normal valve development. The proposed roles are that Wnt sequentially a) promotes endocardial-mesenchymal transformation (EMT) to populate the endocardial cushions of the proximal outflow tract, b) acts as a mitogen to support the expansion of cushion mesenchyme in all valves and subsequently directs local cell proliferation to promote valve elongation, and c) patterns valve leaflets into stratified layers. A tissue-specific, inducible loss-of-function approch in mice will be used to test these hypotheses through three aims: 1) Determine the mechanism by which Wnt induces EMT in the proximal outflow tract, 2) Determine the role of Wnt signals in supporting the expansion of early valve mesenchyme and elongation of the forming valves, and 3) Determine if Wnt signals act as a tissue morphogen to direct stratification of the valve and establish the leaflet- chordae tendineae boundary in the mitral valve during late valvulogenesis. Congenital heart valve defects are among the most common birth defects in the United States and yet the molecular mechanisms underlying these diseases remain unclear. The proposed research will define Wnt-interacting regulatory networks driving key, poorly understood steps in valve development. An improved understanding of the mechanisms underlying normal valvulogenesis will provide insights into the causes of congenital valve defects and support future regenerative medicine approaches for common valve diseases.
Public Health Relevance Developmental defects of the heart valves are among the most common types of heart malformations affecting both children and adults. There are no drug treatments for congenital valve diseases and many affected individuals require invasive tissue repair or replacement surgeries. A better understanding of the molecular and genetic control of valve development would improve genetic counseling for affected families and facilitate the development of innovative regenerative therapies.