Intrauterine growth retardation (IUGR) is a major risk factor for peri-natal mortality and physical and mental retardation. While the causes of IUGR are highly heterogeneous, a strong correlation exists between IUGR caused by retarded placental development and reduced placental epidermal growth factor receptor (EGFR) activation. Therefore, a thorough understanding of EGFR function during placental development is required in order to accurately interpret the causes, identify genetic risk factors, and to design treatments for IUGR. To analyze the role of Egfr during placental development, an extensive and highly integrated genetic and molecular analysis of Egfr function will be pursued. The proposed experiments will use innovative approaches to study the dependency of the Egfr null phenotype on the genetic background. The modifier genes underlying the background dependency will be regionally mapped using a series of inbred mouse strains that have shown a modification of the placental phenotype (Specific Aim 1). These studies will be augmented by detailed histological and gene expression microarray analysis (Specific Aim 2) and phenotypic analysis of an engineered Egfr allelic series (Specific Aim 3) to provide a detailed biological context for successful candidate gene cloning and validation of the modifiers (Specific Aim 4). Through a detailed analysis of Egfr function using this mouse model, we will gain a much deeper insight into how EGFR functions in human placental development and how, through genetic modifiers, the severity of IUGR is modified. Additionally, knowing the types of genes that can compensate for abnormal Egfr function may lead to targets for IUGR therapeutic intervention. Treatments for IUGR would increase the chances of a successful pregnancy and greatly enhance post-natal survival and quality of life for the affected neonates.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Project (R01)
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Study Section
Mammalian Genetics Study Section (MGN)
Program Officer
Ilekis, John V
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University of North Carolina Chapel Hill
Schools of Medicine
Chapel Hill
United States
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Lee, Tang-Cheng; Threadgill, David W (2009) Generation and validation of mice carrying a conditional allele of the epidermal growth factor receptor. Genesis 47:85-92
Dackor, Jennifer; Caron, Kathleen M; Threadgill, David W (2009) Placental and embryonic growth restriction in mice with reduced function epidermal growth factor receptor alleles. Genetics 183:207-18
Barrick, Cordelia J; Roberts, Reade B; Rojas, Mauricio et al. (2009) Reduced EGFR causes abnormal valvular differentiation leading to calcific aortic stenosis and left ventricular hypertrophy in C57BL/6J but not 129S1/SvImJ mice. Am J Physiol Heart Circ Physiol 297:H65-75
Dackor, Jennifer; Li, Manyu; Threadgill, David W (2009) Placental overgrowth and fertility defects in mice with a hypermorphic allele of epidermal growth factor receptor. Mamm Genome 20:339-49
Barrick, Cordelia J; Yu, Ming; Chao, Hann-Hsiang et al. (2008) Chronic pharmacologic inhibition of EGFR leads to cardiac dysfunction in C57BL/6J mice. Toxicol Appl Pharmacol 228:315-25
Dackor, J; Strunk, K E; Wehmeyer, M M et al. (2007) Altered trophoblast proliferation is insufficient to account for placental dysfunction in Egfr null embryos. Placenta 28:1211-8
Barrick, Cordelia J; Rojas, Mauricio; Schoonhoven, Robert et al. (2007) Cardiac response to pressure overload in 129S1/SvImJ and C57BL/6J mice: temporal- and background-dependent development of concentric left ventricular hypertrophy. Am J Physiol Heart Circ Physiol 292:H2119-30
Hsieh, Minnie; Lee, Daekee; Panigone, Sara et al. (2007) Luteinizing hormone-dependent activation of the epidermal growth factor network is essential for ovulation. Mol Cell Biol 27:1914-24
Lee, Daekee; Pearsall, R Scott; Das, Sanjoy et al. (2004) Epiregulin is not essential for development of intestinal tumors but is required for protection from intestinal damage. Mol Cell Biol 24:8907-16
Strunk, Karen E; Amann, Vicky; Threadgill, David W (2004) Phenotypic variation resulting from a deficiency of epidermal growth factor receptor in mice is caused by extensive genetic heterogeneity that can be genetically and molecularly partitioned. Genetics 167:1821-32

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