The long term objective of this research is to obtain a complete understanding of the genetic and molecular mechanisms underlying two hereditary forms of congenital heart disease: Conotruncal defects (CTDs) and patent ductus arteriosus (PDA). These will be studied in embryos and fetuses of unique lines that are accurate models of the human defects. In the CTD line, the following specific hypotheses will be tested: 1. Abnormal development of the conotruncal septum, producing ventricular septal defect, tetralogy of Fallot, or persistent truncus arteriosus, is associated with a generalized failure of growth of right ventricular myocardium in early embryos; 2) There is abnormal expression of myosin ventricular light chains in the affected myocardium; 3) A single major gene mutation underlies the CTD line defect and this gene may have identity with or be linked to myosin gene loci. In the PDA line, the following hypotheses will be tested: 1) The failure of intimal thickening in the ductus arteriosus of affected PDA line fetuses is associated with a genetically-determined block in the accumulation of hyaluronic acid (HA) in the subintimal region; 2) Ductus arteriosus (DA) specific protein molecules recently identified in endothelial and smooth muscle cells of the normal lamb DA are present in normal dog DA but one or both is absent in the hereditary PDA line dogs. Methods to be used include quantitative morphometry and BrdU-labelling of mitotic cells of the myocardium and cushion tissue of the embryonic heart, analysis of the distribution of myosin light chains in embryonic and fetal myocardium using protein gel electrophoresis (1D, 2D PAGE) and antibodies against these proteins, DNA Southern blot restriction fragment length polymorphism (RFLP) studies of linkage of the CTD gene to myosin genes and other genes. PDA studies include immunohistochemical and biochemical analysis of HA in the fetal and neonatal ductus arteriosus during intimal thickening, cell cultures analysis of radiolabeled proteins of DA, pulmonary artery, and aortic cells by SDS PAGE and autoradiography, and use of monospecific antibodies to study the distribution of the ductus-specific proteins in situ.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37HL018848-17
Application #
3485601
Study Section
Cardiovascular and Pulmonary Research A Study Section (CVA)
Project Start
1977-05-01
Project End
1994-04-30
Budget Start
1992-05-01
Budget End
1993-04-30
Support Year
17
Fiscal Year
1992
Total Cost
Indirect Cost
Name
University of Pennsylvania
Department
Type
Schools of Veterinary Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Werner, Petra; Raducha, Michael G; Prociuk, Ulana et al. (2008) A novel locus for dilated cardiomyopathy maps to canine chromosome 8. Genomics 91:517-21
Werner, Petra; Raducha, Michael G; Prociuk, Ulana et al. (2005) The keeshond defect in cardiac conotruncal development is oligogenic. Hum Genet 116:368-77
Werner, P; Raducha, M G; Shin, D et al. (2004) Assignment of 10 canine genes to the canine linkage and comparative maps. Anim Genet 35:249-51
Buchanan, James W; Patterson, Donald F (2003) Etiology of patent ductus arteriosus in dogs. J Vet Intern Med 17:167-71
Buchanan, J W (2001) Pathogenesis of single right coronary artery and pulmonic stenosis in English Bulldogs. J Vet Intern Med 15:101-4
Otto, C M; Rieser, T M; Brooks, M B et al. (2000) Evidence of hypercoagulability in dogs with parvoviral enteritis. J Am Vet Med Assoc 217:1500-4
Mellersh, C S; Hitte, C; Richman, M et al. (2000) An integrated linkage-radiation hybrid map of the canine genome. Mamm Genome 11:120-30
Werner, P; Mellersh, C S; Raducha, M G et al. (1999) Anchoring of canine linkage groups with chromosome-specific markers. Mamm Genome 10:814-23
Werner, P; Raducha, M G; Prociuk, U et al. (1999) Comparative mapping of the DiGeorge region in the dog and exclusion of linkage to inherited canine conotruncal heart defects. J Hered 90:494-8
Werner, P; Raducha, M G; Prociuk, U et al. (1999) A comparative approach to physical and linkage mapping of genes on canine chromosomes using gene-associated simple sequence repeat polymorphisms illustrated by studies of dog chromosome 9. J Hered 90:39-42

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