The overall objective of this research program is to identify molecular mechanisms that are triggered by uteroplacental insufficiency and lead to adult disease. Human uteroplacental insufficiency causes intrauterine growth retardation, which is associated with adult onset insulin resistance and dyslipidemia independent of social and racial status. Rats rendered IUGR by maternal uteroplacental insufficiency are characterized by altered gene expression of fatty acid metabolizing enzymes prior to the onset of adult hyperglycemia and hypertriglyceridemia. The altered gene expression occurs long after the initial insult and thereby suggests an epigenetic phenomenon. DNA methylation is an important mammalian epigenetic mechanism, and our laboratory has generated preliminary data that demonstrates DNA methylation is altered in the IUGR rat fetus. We therefore hypothesize that uteroplacental insufficiency in the rat and subsequent IUGR alters hepatic and skeletal muscle fetal DNA methylation in a tissue-specific manner, and these changes lead to significant changes in gene expression in the mature rat. To fully test this hypothesis, we propose the following Specific Aims: (1) We will determine the effect uteroplacental insufficiency has upon the process of overall DNA methylation in fetal skeletal muscle and liver; (2) We will investigate fetal DNA methylation differences in specific genes based upon our preliminary data from IUGR fetal skeletal muscle and liver; (3) We will examine methylation differences and their effects in 21 day old and 120 day old control and IUGR rat liver and skeletal muscle. The proposed investigation will identify a molecular mechanism and a specific subset of genes that are altered by the IUGR fetal environment, and it will establish the persistent effect of this mechanism upon these genes. The knowledge gained from this proposal will be used to focus further studies upon the genes and pathways involved using knock in/knock out transgenic technology and may be applicable to screening human IUGR DNA to determine which infants are at high risk to develop the adult morbidities associated with IUGR.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD041075-06
Application #
7093534
Study Section
Human Embryology and Development Subcommittee 1 (HED)
Program Officer
Grave, Gilman D
Project Start
2002-04-01
Project End
2007-03-31
Budget Start
2006-04-01
Budget End
2007-03-31
Support Year
6
Fiscal Year
2006
Total Cost
$295,623
Indirect Cost
Name
University of Utah
Department
Pediatrics
Type
Schools of Medicine
DUNS #
009095365
City
Salt Lake City
State
UT
Country
United States
Zip Code
84112
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Baserga, Mariana; Hale, Merica A; Ke, Xingrao et al. (2006) Uteroplacental insufficiency increases p53 phosphorylation without triggering the p53-MDM2 functional circuit response in the IUGR rat kidney. Am J Physiol Regul Integr Comp Physiol 291:R412-8
Ke, X; Lei, Q; James, S J et al. (2006) Uteroplacental insufficiency affects epigenetic determinants of chromatin structure in brains of neonatal and juvenile IUGR rats. Physiol Genomics 25:16-28

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