Both intrauterine growth restriction (IUGR) and fetal overgrowth increase the risk for perinatal complications and predispose the individual for developing obesity, diabetes and cardiovascular disease in childhood and adult age. Thus, a mechanistic understanding of the regulation of fetal growth is critical for identifying the causes of major pregnancy complications and developmental programming of adult disease. Placental mTOR signaling is inhibited in IUGR and activated in pregnancies complicated by fetal overgrowth. Trophoblast mTOR signaling responds to an array of diverse maternal nutritional and metabolic signals. For example, trophoblast mTOR is activated by insulin/IGF-I, glucose and amino acids, fatty acids and folate, and inhibited by cortisol, adiponectin, infection and reduced uteroplacental blood flow. In addition, mTOR is a positive regulator of trophoblast amino acid and folate transport and mitochondrial respiration. Collectively, this data suggest that trophoblast mTOR signaling functions as a critical hub linking maternal nutrient supply to placental function, fetal growth and developmental programming. However, data demonstrating that changes in trophoblast mTOR signaling directly regulates placental function in vivo, causes abnormal fetal growth and programs adult disease is lacking, representing a major gap in knowledge and a roadblock for future targeting of trophoblast mTOR signaling to mitigate IUGR and fetal overgrowth. Our central hypothesis is that inhibition of trophoblast mTOR signaling is mechanistically linked to decreased placental nutrient transport and mitochondrial respiration, fetal growth restriction and impaired fetal pancreatic islet???cell function. Our approach will be to use gene targeting in cultured primary human trophoblast (PHT) cells and a trophoblast specific inducible mTOR knockdown mouse that we have recently developed.
In Aim 1 we will determine the mechanistic role of trophoblast mTOR signaling in the regulation of placental function and fetal growth. We hypothesize that (1) restoring normal mTOR signaling rescues the phenotype in PHT cells isolated from IUGR pregnancies and that (2) trophoblast-specific mTOR knockdown in mice decreases placental nutrient transport and mitochondrial respiration and inhibits fetal growth.
In Aim 2, we will establish the mechanistic role of trophoblast mTOR signaling in regulating fetal islet function Our working hypothesis is that inhibition of trophoblast mTOR signaling inhibits fetal islet function mediated by exosomal miRNAs released into the fetal circulation. The proposed work is significant because it will generate novel mechanistic information leading to a better understanding of the underpinnings of abnormal fetal growth and in utero programming of metabolic disease, which will have a sustained and significant impact on the field. The proposed work is innovative because the trophoblast specific inducible mTOR knockout mouse, generated using piggyBac transposon mediated transgenesis, represents the first mouse model with inducible trophoblast specific gene targeting.

Public Health Relevance

Abnormal fetal growth affects ~15% of all babies and increases the risk for injuries at delivery and to develop obesity, diabetes, and cardiovascular disease in childhood and later in life. Altered placental function is believed to directly contribute to changes in fetal growth and to better understand the underlying causes of these conditions we will identify key mechanisms regulating placental function and how the placenta directly influences the insulin-secreting cells in the fetus. This research may help design novel treatments to alleviate abnormal fetal growth and its short and long-term adverse consequences.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
2R01HD068370-07
Application #
9991454
Study Section
Pregnancy and Neonatology Study Section (PN)
Program Officer
Ilekis, John V
Project Start
2011-07-25
Project End
2025-03-31
Budget Start
2020-04-01
Budget End
2021-03-31
Support Year
7
Fiscal Year
2020
Total Cost
Indirect Cost
Name
University of Colorado Denver
Department
Obstetrics & Gynecology
Type
Schools of Medicine
DUNS #
041096314
City
Aurora
State
CO
Country
United States
Zip Code
80045
Chen, Yi-Yung; Powell, Theresa L; Jansson, Thomas (2017) 1,25-Dihydroxy vitamin D3 stimulates system A amino acid transport in primary human trophoblast cells. Mol Cell Endocrinol 442:90-97
Rosario, Fredrick J; Powell, Theresa L; Jansson, Thomas (2017) mTOR folate sensing links folate availability to trophoblast cell function. J Physiol 595:4189-4206
Rosario, Fredrick J; Nathanielsz, Peter W; Powell, Theresa L et al. (2017) Maternal folate deficiency causes inhibition of mTOR signaling, down-regulation of placental amino acid transporters and fetal growth restriction in mice. Sci Rep 7:3982
Dimasuay, Kris Genelyn; Aitken, Elizabeth H; Rosario, Fredrick et al. (2017) Inhibition of placental mTOR signaling provides a link between placental malaria and reduced birthweight. BMC Med 15:1
Jansson, Thomas (2016) Placenta plays a critical role in maternal-fetal resource allocation. Proc Natl Acad Sci U S A 113:11066-11068
Dimasuay, Kris Genelyn; Boeuf, Philippe; Powell, Theresa L et al. (2016) Placental Responses to Changes in the Maternal Environment Determine Fetal Growth. Front Physiol 7:12
Rosario, Fredrick J; Dimasuay, Kris Genelyn; Kanai, Yoshikatsu et al. (2016) Regulation of amino acid transporter trafficking by mTORC1 in primary human trophoblast cells is mediated by the ubiquitin ligase Nedd4-2. Clin Sci (Lond) 130:499-512
Gaccioli, Francesca; Aye, Irving L M H; Roos, Sara et al. (2015) Expression and functional characterisation of System L amino acid transporters in the human term placenta. Reprod Biol Endocrinol 13:57
Chen, Yi-Yung; Rosario, Fredrick J; Shehab, Majida Abu et al. (2015) Increased ubiquitination and reduced plasma membrane trafficking of placental amino acid transporter SNAT-2 in human IUGR. Clin Sci (Lond) 129:1131-41
Lager, Susanne; Samulesson, Anne-Maj; Taylor, Paul D et al. (2014) Diet-induced obesity in mice reduces placental efficiency and inhibits placental mTOR signaling. Physiol Rep 2:e00242

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