Coronary disease is a major cause of premature death globally. This condition occurs when the blood vessels supplying the heart become blocked, starving the heart of oxygen needed for the beating heart muscle. An important step in identifying treatments for coronary disease is understanding how coronary vessels develop. The goal of one project in my lab is to determine how the cells of the heart form a complete coronary vascular network during embryonic development. Understanding the process of coronary vessel formation will promote the discovery of treatments for heart disease.
Another project in my laboratory studies the process of left-right axis formation. As the embryonic heart develops the left and right sides must be distinguished because each performs specific functions. If this process is disrupted the heart and lungs will not form the correct connections, resulting in abnormal cardiac function and severe birth defects. Although some of the genes required for this process are known, more remain to be discovered. We have identified a mouse mutant with defects in establishing the left and right sides of the heart. By identifying the mutated gene in these mice, we will find a new genetic factor required for establishing proper left and right-sided heart development.
My research interests combine genetics and developmental biology to identify genes required for cardiovascular development. The heart is the first organ to form during embryogenesis, and proper function of the cardiovascular system is critical for embryonic survival. Additionally, human congenital heart defects occur in 1 in 125 live births. A better understanding of the signals required for proper heart development will provide new avenues for treatment of cardiovascular disease. Research projects in my lab include:
- the characterization of three mutants isolated from a balancer chromosome mutagenesis screen that have defects in different components of the cardiovascular system
- the identification the genes mutated in these lines through positional cloning
- the further analysis of cardiac gene function using molecular biology techniques.
A combination of genetic and developmental biology approaches are used in the laboratory for the characterization of these mutants and the identification of the causative mutation in each line. We have discoverd a role for Erbb2 in atrial electrical conduction. We have also been characterising how the development of the epicardium affects coronary vessel development. Experiments to characterize cardiac laterality and embryonic cardiac function in this mutant are also underway.
A further interest in my laboratory is the genomic organization of the mouse genome. Using complementation test data from regional mouse mutagenesis screens we have studied the density of essential genes in the mouse genome for three genomic intervals. On a genome-wide scale we have investigated the correlation between regions of the genome with highly conserved microsynteny and the presence of essential genes. We have examined the role of essential genes in human disease, and have demonstrated that contrary to prior publications essential genes are invovled in a diverse array of human adult-onset diseases. We have also demonstrated that diseases displaying locus heterogeneity are caused by proteins that are closely associated in protein-protein interaction networks. Further studies in this area, using bioinformatics approaches, are underway to predict which genes are likely to be required for mammalian development. A project funded by Kids Kidney Research is currently studying genes that are mutated in congenital kidney defects.