Accumulating evidence from our laboratory and others suggests that adult diseases originate in utero, and likely occur through the reprogramming of gene expression via epigenetic changes in chromatin structure (altered """"""""histone code"""""""").Uteroplacental insufficiency (UPI) is a significant cause of morbidity in humans that leads to intrauterine growth restriction (IUGR) and increases the risk of serious kidney related adult morbidities, such as hypertension. One mechanism that can lead to hypertension in humans is 11 beta-hydroxysteroid dehydrogenase type 2 (11?-HSD2) deficiency. This enzyme regulates renal steroid sensitivity by metabolizing glucocorticoids to an inactive form in the kidney. Importantly, in a well characterized animal model of IUGR and adult onset hypertension, we have demonstrated persistent decreased levels of kidney 11?-HSD2 levels through juvenile and adult stages. The mechanisms that regulate kidney 11?-HSD2 mRNA levels are largely unknown and constitute the target of the present investigation. In this proposal we hypothesize that IUGR affects kidney epigenetic determinants of chromatin structure in a gene-specific manner resulting in permanent down regulation of 11?-HSD2 expression.
In Aim 1 we will characterize IUGR- induced chromatin modifications of renal 11?-HSD2.
In Aim 2, we will determine how the binding of specific transcription factors can be affected by IUGR and can result in altered expression of 11?-HSD2. Ultimately, these studies will provide a basis for potential dietary and/or specific pharmacological interventions that can reverse or moderate the epigenetic alterations underlying decreased kidney 11?-HSD2.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Small Research Grants (R03)
Project #
5R03HD058782-02
Application #
7666032
Study Section
Pediatrics Subcommittee (CHHD)
Program Officer
Winer, Karen
Project Start
2008-08-01
Project End
2010-06-30
Budget Start
2009-07-01
Budget End
2010-06-30
Support Year
2
Fiscal Year
2009
Total Cost
$75,250
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
Baserga, Mariana; Kaur, Rajwinderjit; Hale, Merica A et al. (2010) Fetal growth restriction alters transcription factor binding and epigenetic mechanisms of renal 11beta-hydroxysteroid dehydrogenase type 2 in a sex-specific manner. Am J Physiol Regul Integr Comp Physiol 299:R334-42
Baserga, Mariana; Bares, Allyson L; Hale, Merica A et al. (2009) Uteroplacental insufficiency affects kidney VEGF expression in a model of IUGR with compensatory glomerular hypertrophy and hypertension. Early Hum Dev 85:361-7