Research Interests
Our laboratory investigates the molecular basis of cardiac morphogenesis and Congenital Heart Disease. Congenital Heart Disease, or structural malformations of the heart present at birth, is the most common class of human birth defects. We employ forward and reverse genetic approaches in the mouse to address the genetic basis of structural heart disease. We use genetic, molecular, and biochemical methods to investigate the specific aspects of cardiac morphogenesis involved in Congenital Heart Disease.
We have initiated a gene discovery program using a forward genetic screen to identify mice with mutations affecting genes required for cardiac morphogenesis. We have established a screening strategy based on the fetal to neonatal circulatory transition. We find this strategy selects for cardiac morphogenesis defects commonly observed in human patients with Congenital Heart Disease. We have identified and mapped mutations resulting in an array of heart defects.
Our initial focus has been on defects of the cardiac valves. From our forward screen, we have mapped mutations from four lines with cardiac valve defects and have cloned one, in a gene implicated in sonic hedgehog signaling. We also employ reverse genetic approaches to investigate early aspects of cardiac valve development. Conditionally removing Smad4 from the endocardium, the primary valve cell set progenitor, results in an early failure of valve development. We are currently investigating the valve stem cell population.
The long-term objective of the work in our laboratory is to (1) Identify genes involved in the aspects of mammalian cardiac morphogenesis pertinent to human Congenital Heart Disease, (2) Understand the role of the identified gene products in cardiac morphogenesis, and (3) Gain a mechanistic understanding of how mutation in the identified genes results in cardiac morphogenetic defects and human Congenital Heart Disease.
