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.
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