Abnormal cardiac inflow tract remodeling can result in total anomalous pulmonary venous return (TAPVR), a life-threatening congenital heart defect. My human genetic studies and my preliminary expression and functional data in chick and mouse embryos suggest that PDGF-signaling is required for inflow tract remodeling and correct pulmonary venous connection. Asymmetric accumulation of cells in the heart stalk is thought to be important for inflow tract and pulmonary vein (PV) development. My data in chick show that Pdgfra and its ligand Pdgfa are expressed in mesenchyme on opposite sides of the heart stalk during PV formation and later around the PV as it matures. I hypothesize that asymmetric expression of PDGF signaling molecules in the heart stalk is required for normal inflow tract and PV development. The transcription factor PITX2 is a key player in asymmetric organogenesis. Mice lacking asymmetric expression of PITX2 have TAPVR. I hypothesize that downstream targets of PITX2 in the heart stalk, likely to include PDGF-signaling molecules, mediate inflow tract remodeling and PV development. My long-term objective is to understand the genetic pathways that regulate inflow tract remodeling and the pulmonary venous connection to the left atrium. I propose the following specific aims 1. Characterize PDGF-signaling in the mouse heart stalk: define the temporal and spatial expression patterns of the PDGF receptors and ligands in the developing mouse heart stalk;determine the requirement of PDGF-signaling in heart stalk patterning and PV development using PDGFRA deficient mouse mutants;examine the cellular mechanisms underlying the leftward shift of the PV. 2. Identify PITX2-regulated genes during mouse inflow tract remodeling: define the expression pattern of PDGF-signaling molecules in Pitx2 mutants lacking an asymmetric enhancer;use these Pitx2AASE mutants to identify PITX2-regulated genes in the inflow tract and heart stalk by microarray analysis. A well structured career development plan, extensively supported with institutional resources and internationally known mentors, has been designed to allow me to transition during the tenure of the K award to an independent tenure-track faculty investigator. Thus, I will receive the necessary training both to direct an active research program and provide state-of-the-art clinical care.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08HL084559-04
Application #
7609148
Study Section
Special Emphasis Panel (ZHL1-CSR-O (F1))
Program Officer
Colombini-Hatch, Sandra
Project Start
2006-04-01
Project End
2011-03-31
Budget Start
2009-04-01
Budget End
2010-03-31
Support Year
4
Fiscal Year
2009
Total Cost
$134,730
Indirect Cost
Name
University of Utah
Department
Pediatrics
Type
Schools of Medicine
DUNS #
009095365
City
Salt Lake City
State
UT
Country
United States
Zip Code
84112
Urness, Lisa D; Bleyl, Steven B; Wright, Tracy J et al. (2011) Redundant and dosage sensitive requirements for Fgf3 and Fgf10 in cardiovascular development. Dev Biol 356:383-97
Bleyl, Steven B; Saijoh, Yukio; Bax, Noortje A M et al. (2010) Dysregulation of the PDGFRA gene causes inflow tract anomalies including TAPVR: integrating evidence from human genetics and model organisms. Hum Mol Genet 19:1286-301
Bax, Noortje A M; Bleyl, Steven B; Gallini, Radiosa et al. (2010) Cardiac malformations in Pdgfralpha mutant embryos are associated with increased expression of WT1 and Nkx2.5 in the second heart field. Dev Dyn 239:2307-17
Bleyl, Steven B; Byrne, Janice L B; South, Sarah T et al. (2007) Brachymesomelic dysplasia with Peters anomaly of the eye results from disruptions of the X chromosome near the SHOX and SOX3 genes. Am J Med Genet A 143A:2785-95
Stevenson, David A; Bleyl, Steven B; Maxwell, Teresa et al. (2007) Mandibulofacial dysostosis in a patient with a de novo 2;17 translocation that disrupts the HOXD gene cluster. Am J Med Genet A 143A:1053-9
Bleyl, S B; Moshrefi, A; Shaw, G M et al. (2007) Candidate genes for congenital diaphragmatic hernia from animal models: sequencing of FOG2 and PDGFRalpha reveals rare variants in diaphragmatic hernia patients. Eur J Hum Genet 15:950-8
Bleyl, Steven B; Botto, Lorenzo D; Carey, John C et al. (2006) Analysis of a Scottish founder effect narrows the TAPVR-1 gene interval to chromosome 4q12. Am J Med Genet A 140:2368-73
Chapman, Susan C; Cai, Qin; Bleyl, Steven B et al. (2006) Restricted expression of Fgf16 within the developing chick inner ear. Dev Dyn 235:2276-81