Deciphering the gene regulatory networks (GRN) that drive differentiation in the developing embryo is essential for identifying mutations that cause th disease and developing novel treatments for congenital defects. Here, I propose to use a combination of high-throughput genomic techniques (Chip-seq and RNA-seq), bioinformatic analyses, molecular techniques, and transgenic zebrafish to begin to elucidate the GRN necessary for the differentiation of the atrioventricular canal (AVC) by identifying the upstream regulators of Tbx2 and Tbx3 and their downstream targets. The AVC is an important player in a number of cardiogenic events including looping, septation, conduction system formation and ultimately cardiac valve differentiation. Therefore, understanding the GRN underlying the mid-gestational differentiation and morphogenesis of the AVC will help identify causative mutations for congenital heart disease, increase our mechanistic understanding of these diseases and eventually may aid the development of novel treatments. This research will also provide important insights into GRN structure and function. The AVC is an excellent model for studying the GRNs involved in organogenesis because it is well defined throughout its formation, has a relatively simple structure and can be embryonically perturbed without causing lethality in zebrafish. This postdoctoral fellowship will provide me with training in zebrafish genetics, cardiac development, bioinformatics and computational analyses of gene regulatory networks.
The atrio-ventricular canal (AVC) is an embryonic structure involved in heart looping, heart chamber formation and valve development. We propose to discover the gene regulatory network that drives AVC differentiation to provide important insights into the underlying causes of congenital heart defects and to improve their treatment.
|Hill, Jonathon T; Demarest, Bradley L; Bisgrove, Brent W et al. (2014) Poly peak parser: Method and software for identification of unknown indels using sanger sequencing of polymerase chain reaction products. Dev Dyn 243:1632-6|