The long-term goal of this project is to enhance the understanding of molecular mechanisms that control cardiac development and maintenance of a normal cardiac phenotype. Identifying and characterizing the transcription factor cascade that controls cardiac development is an important step in understanding the genesis of congenital heart defects and important clinical disorders such as cardiac hypertrophy and heart failure. Malformations of the heart account for the largest number of human birth defects, about 1 % of live births. Despite this high frequency of occurrence, the molecular mechanisms that lead to congenital heart defects remain poorly understood. We have demonstrated that the phenotype of the mutant mice carrying mutations in the jumonji gene (jmj) is similar to human congenital heart diseases and the fetal form of cardiac failure. Therefore, the proposed research plan is to characterize the developmental and molecular function of jmj and its cofactors in cardiovascular development.
Specific Aim 1. We have identified a putative cofactor of JMJ by yeast two hybrid screening. In this aim, we will test the hypothesis that a novel zinc finger protein (Zfp496) is a cofactor of JMJ, which regulates the molecular function of JMJ.
Specific Aim 2 is to analyze phenotypes of mice harboring a lineage-specific knockout of jmj. We have generated conditional jmj knock out mice in a myocardial-, endothelial-, or neural- specific manner using Cre-loxP technology. In this aim, we will test whether JMJ plays important roles in a cell lineage-specific manner within the developing heart.
Specific Aim 3 is to determine the novel downstream genes of JMJ by microarray analyses. We will investigate global changes in the gene expression profiles by an acute deletion of jmj to identify direct target genes of JMJ and by a chronic deletion to assess the cellular/physiological changes occurred in jmj null hearts. The jmj mutant mouse model is clinically significant, because malformations of the heart account for the largest number of human birth defects and physiological roles of JMJ and cofactors are likely to be conserved in human. Therefore, the outcome of this proposal will yield important insights into both the genesis of congenital heart disease and the mechanisms that lead to cardiac hypertrophy and heart failure. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL067050-06
Application #
7256994
Study Section
Cardiovascular Differentiation and Development Study Section (CDD)
Program Officer
Schramm, Charlene A
Project Start
2001-04-01
Project End
2010-05-31
Budget Start
2007-06-01
Budget End
2008-05-31
Support Year
6
Fiscal Year
2007
Total Cost
$345,732
Indirect Cost
Name
University of Wisconsin Madison
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715
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Brody, Matthew J; Feng, Li; Grimes, Adrian C et al. (2016) LRRC10 is required to maintain cardiac function in response to pressure overload. Am J Physiol Heart Circ Physiol 310:H269-78
Brody, Matthew J; Cho, Eunjin; Mysliwiec, Matthew R et al. (2013) Lrrc10 is a novel cardiac-specific target gene of Nkx2-5 and GATA4. J Mol Cell Cardiol 62:237-46
Lee, Min Jae; Kim, Dong Eun; Zakrzewska, Adriana et al. (2012) Characterization of arginylation branch of N-end rule pathway in G-protein-mediated proliferation and signaling of cardiomyocytes. J Biol Chem 287:24043-52
Brody, Matthew J; Hacker, Timothy A; Patel, Jitandrakumar R et al. (2012) Ablation of the cardiac-specific gene leucine-rich repeat containing 10 (Lrrc10) results in dilated cardiomyopathy. PLoS One 7:e51621
Mysliwiec, Matthew R; Carlson, Clayton D; Tietjen, Josh et al. (2012) Jarid2 (Jumonji, AT rich interactive domain 2) regulates NOTCH1 expression via histone modification in the developing heart. J Biol Chem 287:1235-41
Mysliwiec, Matthew R; Bresnick, Emery H; Lee, Youngsook (2011) Endothelial Jarid2/Jumonji is required for normal cardiac development and proper Notch1 expression. J Biol Chem 286:17193-204
Mejetta, Stefania; Morey, Lluis; Pascual, Gloria et al. (2011) Jarid2 regulates mouse epidermal stem cell activation and differentiation. EMBO J 30:3635-46
Zhang, Zhuo; Jones, Amanda; Sun, Chiao-Wang et al. (2011) PRC2 complexes with JARID2, MTF2, and esPRC2p48 in ES cells to modulate ES cell pluripotency and somatic cell reprogramming. Stem Cells 29:229-40
Carlson, Clayton D; Warren, Christopher L; Hauschild, Karl E et al. (2010) Specificity landscapes of DNA binding molecules elucidate biological function. Proc Natl Acad Sci U S A 107:4544-9

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