The Role of DEPTOR in Intrauterine Growth Restriction
Date
2021
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Abstract
Maternal obesity or insufficient nutrient supply during pregnancy can result in fetal overgrowth and fetal growth restriction, respectively, and cause serious health problems for both the mother and the fetus. Dysregulated placental nutrient transport is believed to be a mediator for both conditions. The mammalian target of rapamycin (mTOR) is thought to be the nutrient sensor of the placenta. mTOR is comprised of two complexes, mTORC1 and mTORC2. Both mTORC1 and mTORC2 have downstream targets that regulate cell growth, proliferation, ion transport, cytoskeletal remodeling, and more. Intrauterine Growth Restriction (IUGR) is associated with decreased nutrient transport and restricted nutrient availability for the fetus. It has been shown that mTOR is downregulated in placentas of pregnancies complicated by IUGR. The DEP-domain containing mTOR interacting protein (DEPTOR) has recently been shown to be an endogenous inhibitor of mTOR. We hypothesized that placenta-specific DEPTOR knockdown (KD) results in restoration of mTOTRC1/2 signaling, normalizing placental amino acid transport capacity and preventing IUGR. In the first part of this thesis, we generated a transgenic mouse model that expressed a placenta-specific DEPTOR KD cassette to study the in vivo effects of placental DEPTOR KD. Results showed that trophoblastic DEPTOR inhibition leads to increased expression of mTORC1/2 signaling, increased activity of the two main placental amino acid transport systems, and a marked increase in birth weight. In the second part of this thesis, we aimed to optimize parameters for placental sonoporation, a minimally invasive in vivo gene delivery technique that utilizes ultrasound and DNA conjugated lipid microbubbles. We observed successful placental transgene expression after sonoporation following intravenous injection of DNA conjugated lipid microbubbles. Taken together, this thesis has elucidated the role of placental DEPTOR in the regulation of mTORC1/2 signaling and fetal nutrient transport, providing insight into the molecular mechanisms that govern fetal growth and, ultimately, health. Furthermore, the successful sonoporation trials illustrate the possibility for this technique to be used as an alternative to transgenics for studying in vivo gene modulation, as well as a potential adaptable technique for the treatment of complications due to placental dysregulation.
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Developmental biology, Molecular biology, Biomedical engineering, DEPTOR, mTOR, Placenta, Sonoporation
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100 pages
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