Placental development is a complex process that involves interactions among multiple cell types and may be affected by maternal nutrition during pregnancy. Further, the fetal origins of adult disease hypothesis posits that maternal nutrition during pregnancy has consequences for the future adult health ofthe fetus. In particular, it has been shown that severe caloric restriction during early pregnancy results in increased risk of obesity and cardiovascular disease when the affected fetus reaches middle age. The mechanisms by which this occurs are poorly understood, but the timing suggests that altered placental development may be involved. The hypothesis underlying this proposal is that the hormone leptin influences multiple steps in the process of placental development. Leptin is produced by fat cells, and thus is a potential mediator ofthe effects of nutrition on placental development and subsequent adult health. The first specific aim is to determine whether leptin shortage mediates effects of nutrition on fetal and placental programming. Animals will be placed on a restricted diet with or without leptin replacement, and effects on placental development and adult adiposity determined. Placental size, morphology, gene expression, and gene methylation will be examined. In addition, the offspring of treated mothers will be followed through adulthood to determine longterm effects of diet and leptin replacement on obesity and lipid profiles. The second specific aim is to determine effects of leptin on placental differentiation at the cellular level. Trophoblast stem cells will be used to study the role of leptin in the differentiation of giant cell, syncytiotrophoblast cell, and spongiotrophoblast cell types. In addition to the scientific aims ofthe proposal, a goal of this """"""""Pathways to Independence"""""""" project is to establish an independent laboratory in reproductive biology to pursue research on the effects of maternal environment on placental development.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Transition Award (R00)
Project #
5R00HD055231-05
Application #
8137077
Study Section
Special Emphasis Panel (NSS)
Program Officer
Ilekis, John V
Project Start
2008-05-15
Project End
2013-06-30
Budget Start
2011-07-01
Budget End
2013-06-30
Support Year
5
Fiscal Year
2011
Total Cost
$241,661
Indirect Cost
Name
University of Missouri-Columbia
Department
Veterinary Sciences
Type
Schools of Earth Sciences/Natur
DUNS #
153890272
City
Columbia
State
MO
Country
United States
Zip Code
65211
Harper, Jennifer L; Caesar, Gerialisa A; Pennington, Kathleen A et al. (2015) Placental changes caused by food restriction during early pregnancy in mice are reversible. Reproduction 150:165-72
PrabhuDas, Mercy; Bonney, Elizabeth; Caron, Kathleen et al. (2015) Immune mechanisms at the maternal-fetal interface: perspectives and challenges. Nat Immunol 16:328-34
Pennington, Kathleen A; Harper, Jennifer L; Sigafoos, Ashley N et al. (2012) Effect of food restriction and leptin supplementation on fetal programming in mice. Endocrinology 153:4556-67
Pennington, Kathleen A; Schlitt, Jessica M; Jackson, Daniel L et al. (2012) Preeclampsia: multiple approaches for a multifactorial disease. Dis Model Mech 5:9-18
Schlitt, Jessica M; Schulz, Laura C (2012) The source of leptin, but not leptin depletion in response to food restriction, changes during early pregnancy in mice. Endocrine 41:227-35
Pennington, Kathleen A; Schlitt, Jessica M; Schulz, Laura C (2012) Isolation of primary mouse trophoblast cells and trophoblast invasion assay. J Vis Exp :e3202
Schulz, Laura Clamon; Schlitt, Jessica M; Caesar, Gerialisa et al. (2012) Leptin and the placental response to maternal food restriction during early pregnancy in mice. Biol Reprod 87:120
Schulz, Laura C; Roberts, R Michael (2011) Dynamic changes in leptin distribution in the progression from ovum to blastocyst of the pre-implantation mouse embryo. Reproduction 141:767-77
Aubuchon, Mira; Schulz, Laura C; Schust, Danny J (2011) Preeclampsia: animal models for a human cure. Proc Natl Acad Sci U S A 108:1197-8
Schulz, Laura C (2010) The Dutch Hunger Winter and the developmental origins of health and disease. Proc Natl Acad Sci U S A 107:16757-8

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