Department of Pediatrics

E-mail: steven.bleyl@utah.edu
Address: 30 N. 1900 E., Room 2R063 SOM
Phone: 587-3604

Research Title:  The inheritance of TAPVR is thought to involve complex genetic and/or environmental factors.

Research Description:

TAPVR is a life-threatening congenital heart defect that affects 1 in 15,000 live births and is fatal in the first year if not surgically corrected. The inheritance of TAPVR is thought to involve complex genetic and/or environmental factors. Although the embryology of normal pulmonary vein development is well described, there is little in the literature about the embryogenesis or molecular pathogenesis of TAPVR. I previously reported a 2.4 Mb locus for isolated TAPVR at chromosome 4q12 discovered through linkage and founder effect mapping. Further analysis of founder haplotypes across this interval narrowed this locus to the non-coding region between the PDGFRA and KIT genes, implicating defective regulation of a neighboring gene(s) in the development of TAPVR. Expression analysis of the nearby PDGFRA gene in both chick and mouse shows expression to the right of the pulmonary vein during its transfer to the left atrium. Later in development, PDGFRA is expressed on the right half of the remnant of the dorsal mesocardium that connects the pulmonary vein to the inflow tract. The PDGF-A ligand is also expressed in a temporal and spatial manner supporting a role for PDGF-signaling in pulmonary vein development. To test the hypothesis that PDGF signaling is required for correct connection of the pulmonary vein, we used an in ovo function blocking assay in chick and a conditional knockout approach in mouse. We show, in both organisms, that loss of PDGFRA function leads to a spectrum of inflow tract defects, including TAPVR. This animal model of TAPVR, the first reported, provides important insight into the pathogenesis of anomalous pulmonary vein development.

Opportunities for medical student research in our lab include:

• Work in model organisms (chick or mouse) to identify and characterize novel genes involved in pulmonary vein/inflow tract remodeling. The student would learn basic techniques in developmental biology and experimental embryology.

• Work with human genetics with TAPVR patients. The student would use high throughput SNP geneotyping techniques to examine sporadic and familial cases of TAPVR for founder-effect haplotypes. This work has the potential of identifying new TAPVR loci.

• Work in 3D digital reconstruction/computer imaging. Data recently collected via our collaboration with the Kyoto Human Embryo collection will be assembled to create a 3D stage series of normal pulmonary vein development. Work with small animal MRI to characterize normal and abnormal pulmonary veins could also be examined.

Mentoring and Lab environment:

As a new faculty member, I have no experience mentoring medical students. BUT, the Bleyl lab is currently partnered with the larger lab of Gary Schoenwolf, PhD, who has extensive mentoring experience. Medical student researchers would interact with three technicians, five postdoctoral fellows and undergraduate researchers in the lab. They would benefit from involvement in weekly lab meetings and by attendance to various research conferences in the Departments of Pediatrics, Neurobiology and Anatomy and others.

Does this research involve human subjects or animals?

If yes, what is the protocol number?

1/2008