Intrauterine growth restriction (IUGR) is a common, biologically important condition with individuals at risk of developing multiple morbidities, including chronic lung disease (CLD) and adult obesity. These morbidities both involve the transcription factor PPARg. PPARg is also responsive to fatty acids, such as DHA. We have shown that PPARg mRNA is affected differently in lung and adipose tissue in response to rat IUGR. The central hypothesis of this proposal is that IUGR alters the epigenetic profile of the PPARg gene consistent with tissue- specific changes in PPARg mRNA. We also hypothesize that maternal DHA supplementation normalizes changes to the epigenetic profile of PPARg in the offspring, via activation of PPARg. To test these hypotheses, we propose two specific aims. 1) IUGR will alter the epigenetic profile of the PPARg gene in lung and adipose tissue of rats in a tissue-specific way. This will provide the first set of in vivo data correlating epigenetic profiles with mRNA levels. 2) DHA added to the maternal diet ablates the IUGR induced change in the epigenetic profile of PPARg in the offspring, via the activation of PPARg. This will use a dietary intervention that normalizes PPARg mRNA to further assess mechanisms of the epigenetic modifications to the PPARg gene. This research is innovative because understanding the epigenetic regulation of PPARg, and manipulating its expression, provides a powerful tool to affect PPARg targets. Given that PPARg has crucial roles in the IUGR induced morbidities CLD and obesity, and that IUGR alters PPARg mRNA in the lung and adipose, an understanding of the transcriptional regulation of PPARg in IUGR will be necessary for a mechanistic understanding of the formation of the IUGR phenotype as well as meaningful interventions. This research program will complement the Career Development Plan (CDP) and enable the candidate to meet the following short-term career goals 1) understand the transcriptional regulation of PPARg in IUGR and explore DHA as an activator of PPARg and a nutritional intervention and 2) understand of the problems, processes and vocabulary of the clinical arena. The CDP will take place under the mentorship of Dr Robert Lane, an NIH funded researcher and expert on the effect of intrauterine growth restriction (IUGR) on epigenetics. This research, combined with the proposed didactic training, will facilitate the transition of the candidate to an independent biomedical researcher. Data generated by this proposal will form the basis for a future R01 proposal examining the mechanisms by which down-stream effects of PPARg alter epigenetics in utero. This data will also provide an opportunity to further develop targeted nutritional and pharmaceutical interventions to improve the IUGR phenotype.

Public Health Relevance

Intrauterine growth restriction is a common, biologically important condition with individuals at risk of multiple morbidities, including chronic lung disease (CLD) and adult obesity. When inappropriately regulated, PPARg, contributes to these IUGR related diseases. This project aims to uncover the mechanisms of inappropriate PPARg regulation and identifies a dietary intervention that potentially improves the consequences of IUGR.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Scientist Development Award - Research & Training (K01)
Project #
5K01DK084036-03
Application #
8318233
Study Section
Diabetes, Endocrinology and Metabolic Diseases B Subcommittee (DDK)
Program Officer
Hyde, James F
Project Start
2010-09-30
Project End
2013-08-31
Budget Start
2012-09-01
Budget End
2013-08-31
Support Year
3
Fiscal Year
2012
Total Cost
$106,594
Indirect Cost
$7,896
Name
University of Utah
Department
Pediatrics
Type
Schools of Medicine
DUNS #
009095365
City
Salt Lake City
State
UT
Country
United States
Zip Code
84112
Ke, Xingrao; Xing, Bohan; Yu, Baifeng et al. (2014) IUGR disrupts the PPAR?-Setd8-H4K20me(1) and Wnt signaling pathways in the juvenile rat hippocampus. Int J Dev Neurosci 38:59-67
Joss-Moore, Lisa; Carroll, Travis; Yang, Yan et al. (2013) Intrauterine growth restriction transiently delays alveolar formation and disrupts retinoic acid receptor expression in the lung of female rat pups. Pediatr Res 73:612-20
Zinkhan, Erin K; Fu, Qi; Wang, Yan et al. (2012) Maternal Hyperglycemia Disrupts Histone 3 Lysine 36 Trimethylation of the IGF-1 Gene. J Nutr Metab 2012:930364
Joss-Moore, Lisa A; Wang, Yan; Yu, Xing et al. (2011) IUGR decreases elastin mRNA expression in the developing rat lung and alters elastin content and lung compliance in the mature rat lung. Physiol Genomics 43:499-505
Joss-Moore, Lisa A; Wang, Yan; Ogata, Elizabeth M et al. (2011) IUGR differentially alters MeCP2 expression and H3K9Me3 of the PPAR? gene in male and female rat lungs during alveolarization. Birth Defects Res A Clin Mol Teratol 91:672-81
Joss-Moore, Lisa A; Albertine, Kurt H; Lane, Robert H (2011) Epigenetics and the developmental origins of lung disease. Mol Genet Metab 104:61-6