Pediatric cardiomyopathy (CM) is a common cause of death and morbidity. Although multiple etiologies are known, until recently, the majority of cases were termed """"""""idiopathic"""""""". Now, it is recognized that CM is familial in 20-50% of adult patients. In dominantly-inherited hypertrophic CM (HCM), single gene defects have been defined. Delineation of genetic causes of pediatric dilated CM, however, is virtually limited to those genes associated with muscular dystrophies. Our laboratory has documented mutations in mitochondrial proteins of the fatty acid oxidation pathways as causes of both HCM, DCM, and sudden expected death. Extensive searches for genetic causes of pediatric M have not been done. Therefore, this proposal will explore the hypothesis that pediatric cardiomyopathy often has a genetic has a genetic etiology, especially secondary to defects in cardiac energy production and develop animal models to determine the molecular pathogenesis of these CMs through four aims.
Aim 1 is to systematically evaluate all pediatric cardiomyopathy patients in St. Louis Children's Hospital for familial causes and genetic etiologies, by clinical, morphologic, and biochemical analyses.
Aim 2 is to characterize the genetic locus in a St. Louis family with dominantly-inherited DCM, with the long term goal of definition mutations in the responsible gene.
Aim 3 is to delineate mutations in nuclear genes encoding the human fatty acid beta-oxidation transporters and enzymes causing pediatric CM, including those in very-long-chain acyl-CoA dehydrogenase, long-chain acyl CoA dehydrogenase, both subunits of the trifunctional protein, and carnitine palmitoyl-transferase II.
This aim will test whether genotype phenotype correlations exist for these deficiency states.
Aim 4 is to define the pathogenesis of CM in fatty acid oxidation defects through creation of mouse models of deficiency by gene ablation techniques and by physiologic and biochemical characterization of deficient animals. Through delineation of genes causing pediatric cardiomyopathy and analysis of mechanisms of myocardial and analysis of the mechanisms of myocardial dysfunction and sudden death in animal models of these genetic defects, a better understanding of proteins essential for cardiac function and adaptation should be forthcoming.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Specialized Center (P50)
Project #
5P50HL061006-02
Application #
6302521
Study Section
Project Start
2000-01-01
Project End
2000-12-31
Budget Start
1998-10-01
Budget End
1999-09-30
Support Year
2
Fiscal Year
2000
Total Cost
$188,328
Indirect Cost
Name
Washington University
Department
Type
DUNS #
062761671
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Jay, Patrick Y; Bielinska, Malgorzata; Erlich, Jonathan M et al. (2007) Impaired mesenchymal cell function in Gata4 mutant mice leads to diaphragmatic hernias and primary lung defects. Dev Biol 301:602-14
Bielinska, M; Kiiveri, S; Parviainen, H et al. (2006) Gonadectomy-induced adrenocortical neoplasia in the domestic ferret (Mustela putorius furo) and laboratory mouse. Vet Pathol 43:97-117
Broekelmann, Thomas J; Kozel, Beth A; Ishibashi, Hideaki et al. (2005) Tropoelastin interacts with cell-surface glycosaminoglycans via its COOH-terminal domain. J Biol Chem 280:40939-47
Thomassin, Laetitia; Werneck, Claudio C; Broekelmann, Thomas J et al. (2005) The Pro-regions of lysyl oxidase and lysyl oxidase-like 1 are required for deposition onto elastic fibers. J Biol Chem 280:42848-55
Bielinska, Malgorzata; Genova, Elena; Boime, Irving et al. (2005) Gonadotropin-induced adrenocortical neoplasia in NU/J nude mice. Endocrinology 146:3975-84
Chiu, Hsiu-Chiang; Kovacs, Attila; Blanton, Robert M et al. (2005) Transgenic expression of fatty acid transport protein 1 in the heart causes lipotoxic cardiomyopathy. Circ Res 96:225-33
Ketola, Ilkka; Otonkoski, Timo; Pulkkinen, Mari-Anne et al. (2004) Transcription factor GATA-6 is expressed in the endocrine and GATA-4 in the exocrine pancreas. Mol Cell Endocrinol 226:51-7
Spiekerkoetter, Ute; Khuchua, Zaza; Yue, Zou et al. (2004) General mitochondrial trifunctional protein (TFP) deficiency as a result of either alpha- or beta-subunit mutations exhibits similar phenotypes because mutations in either subunit alter TFP complex expression and subunit turnover. Pediatr Res 55:190-6
Kozel, Beth A; Ciliberto, Christopher H; Mecham, Robert P (2004) Deposition of tropoelastin into the extracellular matrix requires a competent elastic fiber scaffold but not live cells. Matrix Biol 23:23-34
Peterson 2nd, R A; Kiupel, M; Bielinska, M et al. (2004) Transcription factor GATA-4 is a marker of anaplasia in adrenocortical neoplasms of the domestic ferret (Mustela putorius furo). Vet Pathol 41:446-9

Showing the most recent 10 out of 49 publications