The long term objectives of this proposal are to determine how human placental villi function normally and to dissect how placental dysfunction predisposes to intrauterine growth restriction, a condition implicated in developmental delay and neurobehavioral disorders during childhood.
The Specific Aims are: (1) to determine if the sub-cellular propagation of apoptosis in human syncytiotrophoblasts is spatially transduced through adjacent regions, or via specific organelles, (2) to characterize the role of p53, Bak, and Bad in the unique pattern of apoptotic signal transmission in syncytiotrophoblasts, (3) to dissect the differences in the sub-cellular propagation of apoptosis in syncytiotrophoblasts of villi from pregnancies with intrauterine growth restriction, compared to normal controls. Intact placental function depends on syncytiotrophoblasts that provide an anatomical barrier to interface the fetal and maternal circulations. This unique syncytial epithelium regulates nutrient transport and secretion of hormones to maintain pregnancy and sustain fetal growth. Clinically relevant stressors, such as hypoxia, homocysteine, and the cytokine tumor necrosis factor-alpha, adversely affect constitutive apoptotic turnover of syncytiotrophoblasts and jeopardizes the functional integrity of the trophoblast layer. This proposal is part of our continuing effort to dissect the cellular and molecular mechanisms that underlie human trophoblast apoptosis, injury, and adaptation. We note that placental under-perfusion and exposure to toxic agents impact the occurrence and propagation of trophoblast apoptotic turnover. We use the cutting edge technologies of confocal microscopic imaging, live cell imaging techniques, and siRNA gene suppression to dissect and analyze the spatial and temporal propagation of apoptosis in vitro in cultured syncytiotrophoblasts and in villous syncytiotrophoblasts derived from in vivo specimens. We analyze the roles of key mediators, p53, Bak and Bad, in apoptotic propagation in trophoblasts. Conclusions from our research will not only shed light on normal placental function in human pregnancy but also identify mechanisms by which trophoblast dysfunction contributes to substandard fetal growth. The findings will be critical for development of new tools to identify and manage pregnancies complicated by intrauterine growth restriction.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD029190-12
Application #
7795909
Study Section
Pregnancy and Neonatology Study Section (PN)
Program Officer
Ilekis, John V
Project Start
1994-05-01
Project End
2012-03-31
Budget Start
2010-04-01
Budget End
2011-03-31
Support Year
12
Fiscal Year
2010
Total Cost
$247,751
Indirect Cost
Name
Washington University
Department
Obstetrics & Gynecology
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Calvert, S J; Longtine, M S; Cotter, S et al. (2016) Studies of the dynamics of nuclear clustering in human syncytiotrophoblast. Reproduction 151:657-71
Chen, B; Zaveri, P G; Longtine, M S et al. (2015) N-myc downstream-regulated gene 1 (NDRG1) mediates pomegranate juice protection from apoptosis in hypoxic BeWo cells but not in primary human trophoblasts. Placenta 36:847-53
Yuen, Ryan K C; Chen, Baosheng; Blair, John D et al. (2013) Hypoxia alters the epigenetic profile in cultured human placental trophoblasts. Epigenetics 8:192-202
Chen, Baosheng; Longtine, Mark S; Nelson, D Michael (2013) Punicalagin, a polyphenol in pomegranate juice, downregulates p53 and attenuates hypoxia-induced apoptosis in cultured human placental syncytiotrophoblasts. Am J Physiol Endocrinol Metab 305:E1274-80
Chen, B; Longtine, M S; Nelson, D M (2013) Pericellular oxygen concentration of cultured primary human trophoblasts. Placenta 34:106-9
Chen, Baosheng; Tuuli, Methodius G; Longtine, Mark S et al. (2012) Pomegranate juice and punicalagin attenuate oxidative stress and apoptosis in human placenta and in human placental trophoblasts. Am J Physiol Endocrinol Metab 302:E1142-52
Longtine, M S; Chen, B; Odibo, A O et al. (2012) Villous trophoblast apoptosis is elevated and restricted to cytotrophoblasts in pregnancies complicated by preeclampsia, IUGR, or preeclampsia with IUGR. Placenta 33:352-9
Bildirici, I; Longtine, M S; Chen, B et al. (2012) Survival by self-destruction: a role for autophagy in the placenta? Placenta 33:591-8
Chen, Baosheng; Longtine, Mark S; Nelson, D Michael (2012) Hypoxia induces autophagy in primary human trophoblasts. Endocrinology 153:4946-54
Longtine, M S; Barton, A; Chen, B et al. (2012) Live-cell imaging shows apoptosis initiates locally and propagates as a wave throughout syncytiotrophoblasts in primary cultures of human placental villous trophoblasts. Placenta 33:971-6

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