Abstract

A large proportion of congenital heart defects are seen in the valves and membranous septa of the heart, which are in part derived from the endocardial cushions. The morphogenesis of the endocardial cushions is a complex process, involving a sequence of basic developmental events. These include cell migration, proliferation, and differentiation. It is the goal of this project to define this developmental sequence in greater detail and to understand the role of specific genes in the process. The major focus is on components of the extracellular matrix. The following questions will be addressed. l) What is the role of the homeobox gene, Hox 7, in the initiation of cushion morphogenesis? This will be addressed by examining the effects of anti-sense deoxyoligonucleotides on cushion morphogenesis and on the expression of extracellular matrix components in heart explant cultures and in ovo. 2) What extracellular matrix molecules are expressed during cushion formation? This will be addressed by immunohistochemistry with a battery of antibodies available in the laboratory and by in situ hybridization in some cases of special interest. 3) What is the developmental effect of blocking the expression of specific extracellular matrix components on cushion morphogenesis? This will be carried out with blocking antibodies, where available, or anti-sense deoxyoligonucleotides. In particular we will focus on hyaluronan and its binding proteins (CD-44 and PG-M), collagen II, and a component of the cardiac jelly (1E12) which has been identified recently in this laboratory. 4) The role of other genes in cushion morphogenesis will be studied subsequently, as they become characterized. 5) What is the contribution of the cushion cells to the tissues and extracellular matrix of the mature valves and septa of the heart? This question will be addressed by immunohistological analysis after in situ labeling of cushion cells with replication-defective, lac-Z labeled retrovirus, followed by the reincubation of the windowed, injected chicken eggs.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Specialized Center (P50)
Project #
5P50HL042266-08
Application #
6242045
Study Section
Project Start
1997-01-01
Project End
1997-12-31
Budget Start
1996-10-01
Budget End
1997-09-30
Support Year
8
Fiscal Year
1997
Total Cost
Indirect Cost

  Institution

Name
University of Iowa
Department
Type
DUNS #
041294109
City
Iowa City
State
IA
Country
United States
Zip Code
52242

  Publications

Wang, Qinchuan; Lin, Jenny Li-Chun; Erives, Albert J et al. (2014) New insights into the roles of Xin repeat-containing proteins in cardiac development, function, and disease. Int Rev Cell Mol Biol 310:89-128
Jongewaard, Ian N; Lauer, Ronald M; Behrendt, Douglas A et al. (2002) Beta 1 integrin activation mediates adhesive differences between trisomy 21 and non-trisomic fibroblasts on type VI collagen. Am J Med Genet 109:298-305
Wang, Qin; Li-Chun Lin, Jenny; Jung-Ching Lin, Jim (2002) A novel TCTG(G/C) direct repeat and an A/T-rich HMG2-binding site control the expression of the rat cardiac troponin T gene. J Mol Cell Cardiol 34:1667-79
Camenisch, Todd D; Molin, Daniel G M; Person, Anthony et al. (2002) Temporal and distinct TGFbeta ligand requirements during mouse and avian endocardial cushion morphogenesis. Dev Biol 248:170-81
Wang, Q; Sigmund, C D; Lin, J J (2000) Identification of cis elements in the cardiac troponin T gene conferring specific expression in cardiac muscle of transgenic mice. Circ Res 86:478-84
Wang, D Z; Reiter, R S; Lin, J L et al. (1999) Requirement of a novel gene, Xin, in cardiac morphogenesis. Development 126:1281-94
Runyan, R B; Wendler, C C; Romano, L A et al. (1999) Utilization of antisense oligodeoxynucleotides with embryonic tissues in culture. Methods 18:316-21
Swiderski, R E; Reiter, R S; Nishimura, D Y et al. (1999) Expression of the Mf1 gene in developing mouse hearts: implication in the development of human congenital heart defects. Dev Dyn 216:16-27
Klewer, S E; Krob, S L; Kolker, S J et al. (1998) Expression of type VI collagen in the developing mouse heart. Dev Dyn 211:248-55
Sheffield, V C; Pierpont, M E; Nishimura, D et al. (1997) Identification of a complex congenital heart defect susceptibility locus by using DNA pooling and shared segment analysis. Hum Mol Genet 6:117-21

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