Principal Investigator/Program Director (Last, first, middle): Lee, Men-JeanProject SummaryFor most human genes, maternal and paternal alleles are bi-allelically expressed. However, a specific subsetof genes are imprinted and mono-allelically expressed. The current dogma is that this embryonic imprint isstable across the lifespan of the organism. Loss of imprinting (LOI) leads to bi-allelic expression of theimprinted gene, potentially causing a doubling of gene dosage or gene dysregulation, resulting in disease.Because the methylation marks of imprinted genes are considered permanent after fertilization, any acquiredchanges in the intrauterine environment may lead to stable transgenerational effects. The regulatorycomplexity of these imprinted gene domains may render them particularly sensitive to environmental changessuch as diet and nutrition. Emerging evidence implicates aberrant imprinting in the pathophysiology of manycommon human diseases, including complications of pregnancy such as intrauterine growth restriction (IUGR)and preeclampsia (PE); and even postnatal disorders such as obesity, cardiovascular disease, and type 2diabetes. We have developed a highly sensitive and quantitative allele-specific PCR analysis to measure LOIin a panel of imprinted genes in the human genome. Using this methodology, we have already determined thatpregnancies complicated by PE and IUGR are associated with dysregulation of a set of imprinted genes in theplacenta. Both of these obstetrical disorders have their origins in an early intrauterine environment associatedwith aberrant placentation and trophoblast invasion. We also have novel evidence to suggest that genomicimprinting patterns are not permanently fixed in placental development. Contrary to the prevailing theory,we hypothesize that patterns of LOI are not static in the human placenta and are subject to developmental andenvironmental influences over the course of pregnancy that predispose to adverse pregnancy outcome. Wenow propose a longitudinal trial as a secondary study to the NuMOM2B Trial to monitor LOI in placentasamples from first trimester CVS to birth and determine which LOI patterns in the first trimester lead to normalpregnancy outcomes and which patterns are predictive of pregnancy complications.Project Description Page 7

Public Health Relevance

; first; middle): Lee; Men-JeanProject NarrativeWe have novel preliminary data to suggest that genomic imprinting in the human placenta takes placeacross gestation and is not permanently fixed in early pregnancy. We seek to confirm this finding in alongitudinal study of loss of imprinting by monitoring placenta samples from chorionic villus samplingin the first trimester and the same respective placentas at birth. We will also explore how differencesin loss of imprinting patterns in first trimester placenta samples may be predictive of pregnancycomplications which can ultimately be developed into a bioassay for adverse pregnancy outcomes.Public Health Relevance Statement Page 8

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Exploratory/Developmental Grants (R21)
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Infectious Diseases, Reproductive Health, Asthma and Pulmonary Conditions Study Section (IRAP)
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Reddy, Uma M
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Columbia University (N.Y.)
New York
United States
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