Patrick Y. Jay, M.D., Ph.D.

Associate Professor

Human and Statistical Genetics Program
Molecular Genetics and Genomics Program
Developmental, Regenerative and Stem Cell Biology Program

  • 314-362-2174

  • 314-286-2787

  • 286-2892

  • 8208

  • 3rd Fl. McDonnell Pediatric Research Building


  • genetics, development, gene expression, heart failure, congenital heart disease

  • Genetics and genomics of cardiac development and heart failure

Research Abstract:

Heterozygous mutations of the cardiac transcription factor Nkx2-5 cause congenital cardiac malformations and atrioventricular block. My laboratory studies the mechanisms of pathogenesis and the function of Nkx2-5 in the embryonic and postnatal heart. Our goal is to develop a full genetic and genomic understanding of congenital heart disease and heart failure, which may in turn suggest novel diagnostic and therapeutic strategies. Specific projects in the lab relate to each of the Nkx2-5 phenotypes in man and mouse.

Cardiac development. Nkx2-5 must regulate and interact with other genes to cause the wide range of congenital heart defects seen in man. We are thus mapping modifier genes that affect the penetrance and phenotype of congenital heart defects in a large-scale linkage analysis project. We have also identified an unusual phenotype in an engineered mouse strain that lacks a conserved domain of the transcription factor and are studying candidate protein-protein interactions.

Postnatal cardiac function and heart failure. Genes that affect embryonic development often have important postnatal functions. We are therefore studying the function of Nkx2-5 in the adult heart and using computational methods to elucidate the logic that governs the transcriptional regulation of Nkx2-5 target genes and of gene expression in heart failure. The combination of computational and molecular biologic analyses is expected to uncover novel transcriptional pathways in the heart and to shed light on the general mechanisms that lead to transcription factor haploinsufficiency phenotypes.

Cardiac conduction system. Pluripotent myocytes in the embryonic heart make a cell fate decision to join the conduction system or contractile myocardium. Nkx2-5 gene dosage determines the number of cells in the cardiac conduction system. Null mutants have none, and heterozygotes have half the normal number. Anatomic hypoplasia of the conduction system can explain at least some of the defects observed in Nkx2-5 loss-of-function mutants. We also discovered that a specific subdomain of the AV node is absent in heterozygous knockout animals. Ongoing work focuses on the mechanisms that Nkx2-5 regulates to determine the number of cells in the conduction system and the function of the missing subdomain in AV node physiology.

Selected Publications:

Winston JB, Erlich JM, Green CA, Aluko A, Kaiser KA, Takematsu M, Barlow RS, Sureka AO, LaPage MJ, Janss LL, Jay PY. Heterogeneity of genetic modifiers ensures normal cardiac development. Circulation 2010 121:1313-21.

Hruz PW, Yan Q, Struthers H, Jay PY. HIV protease inhibitors that block GLUT4 precipitate acute, decompensated heart failure in a mouse model of dilated cardiomyopathy. FASEB J 2008 22:2161-7.

Buerger A, Rozhitskaya O, Sherwood MC, Dorfman AL, Bisping E, Abel ED, Pu WT, Izumo S, Jay PY. Dilated cardiomyopathy resulting from high-level myocardial expression of Cre-recombinase. J Card Fail 2006 12:392-398.

Jay PY, Bielinska M, Erlich JM, Mannisto S, Pu WT, Heikinheimo M, Wilson DB. Impaired mesenchymal cell function in Gata4 mutant mice leads to diaphragmatic hernias and primary lung defects. Dev Biol 2006; 301:602-14.

Jay PY, Harris BS, Maguire CT, Buerger A, Wakimoto H, Tanaka M, Kupershmidt S, Roden DM, Schultheiss TM, O’Brien TX, Gourdie RG, Berul CI, Izumo S. Nkx2-5 mutation causes anatomic hypoplasia of the cardiac conduction system. J Clin Invest 2004 113:1130-1137.

Last Updated: 8/4/2011 10:09:18 AM

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