This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Our understanding of the interplay between the genes and the environment is being greatly enhanced in the post-genome era. There are few settings where the importance of this gene-environment interface is more profound than during intrauterine development, where the """"""""critical windows"""""""" are narrower and where disruption or modification can influence fetal development as well as lead to programming of health throughout the life course. This phenomenon, now known as """"""""fetal programming"""""""", is a model of gene environment interaction and can inform the mechanistic basis of the synergistic effect(s) of the environment and the molecular character of development. Research in fetal programming and many other disciplines is now focusing on the paradigm that gene regulation occurs beyond the DNA sequence. The critical role of epigenetic regulation, the mitotically and meiotically heritable control of gene expression not related to DNA sequence, during development is the subject of this proposal. Our work and others'in cancer and development has demonstrated that epigenetic control is susceptible to stresses and insults from the environment. Among the best characterized of these epigenetic alterations are changes to cellular DNA cytosine methylation, particularly hypomethylation of genomic DNA at specific repetitive elements, and hypermethylation of specific gene promoters leading to their functional inactivation. These alterations are particularly important as biomarkers in human studies because they are functionally related to changes in gene expression, yet exhibit a relative permanence. Examination of the specific molecular character of these epigenetic alterations in perinatal development has been less comprehensive. The placenta plays a crucial role in modulating environmental signals. Crucial placental functions and placental gene expression respond to and are """"""""marked"""""""" by environmental insults. We hypothesize that adverse effects on the intrauterine environment lead to aberrant epigenetic alterations which can be captured in the placental epigenome. We propose that these marks can serve as biomarkers defining a """"""""molecular footprint"""""""" which may be generalizable to a variety of adverse intrauterine conditions. We further hypothesize that these alterations can be used as a marker of the adverse influence of events which occur during gestation. Due to the potential generalizability to other pathologies and the profound effects already demonstrated on adult disease, we will use intrauterine growth restriction (IUGR) as our model to examine alterations to the placental epigenome as markers of intrauterine environment. Our background and the robust patient resources available to the COBRE for Perinatal Biology make us uniquely suited for this investigation.
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