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.
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.
