Novel Roles for Phospholipids in Regulating Placental Function and in the Delivery of DHA to the Fetal Brain.

磷脂在调节胎盘功能和向胎儿大脑输送 DHA 方面的新作用。

• 批准号: 10363536
• 负责人: Theresa L Powell
• 金额: $ 50.11万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10363536
• 关键词: Acyltransferase; Address; Adult; Affect; Amino Acid Transport System A; Amino Acids; Arachidonic Acids; Blood; Blood - brain barrier anatomy; Blood Circulation; Blood specimen; Brain; Cell membrane; Cells; Child Health; Childhood; Choline; Complex; Data; Deposition; Development; Disease; Docosahexaenoic Acids; Enzymes; Epithelial; FRAP1 gene; Fatty Acids; Fatty acid glycerol esters; Fetal Growth; Fetal Growth Retardation; Fetus; Functional disorder; Gene Silencing; Gene Targeting; Gestational Diabetes; Growth; Human; Incubated; Label; Lead; Lentivirus; Life; Link; Lipids; Lysophosphatidylcholines; Measures; Mediating; Mediator of activation protein; Mitochondria; Mus; Nonesterified Fatty Acids; Nutrient; Oleic Acids; Outcome; Phosphatidic Acid; Phospholipase A2; Phospholipids; Physiological; Placenta; Pregnancy; Pregnancy Complications; Protein Biosynthesis; Protein Isoforms; Reporting; Respiration; Role; Signal Transduction; Small Interfering RNA; Stable Isotope Labeling; Syncytiotrophoblast; Testing; Tissues; Transferase; Umbilical Blood; Umbilical vein; Western Blotting; Work; alpha-glycerophosphoric acid; blastocyst; cancer cell; choline transporter; enzyme activity; enzyme pathway; fetal; improved; innovation; inorganic phosphate; knock-down; lipid metabolism; maternal diabetes; novel; placental transfer; trophoblast

PROJECT SUMMARY An adequate placental transfer of lipids is critical for normal fetal growth and brain development, yet the mechanisms involved in placental lipid handling and transport are largely unknown. Many important pregnancy complications such as intrauterine growth restriction (IUGR) and maternal diabetes are associated with disturbances in fetal fat deposition that may contribute to adverse short-and long-term outcomes. Although mechanistic links between placental lipid handling and transport, fetal fat deposition and fetal brain development remain to be established, emerging evidence suggests that these pregnancy complications are associated with altered placental lipid metabolism. The syncytiotrophoblast, the transporting epithelium of the human placenta, mediates the transfer of lipids from the maternal to the fetal circulation. There is now compelling evidence that complex lipid forms are produced in large amounts by the syncytiotrophoblast and are potentially released to the fetus. In particular, primary human trophoblast cells rapidly take up fatty acids and incorporate them to phospholipids. De novo synthesis and remodeling of phospholipids generates a range of biologically active intermediates, including Phosphatidic Acid which regulates mTOR signaling in cancer cells. Phospholipid remodeling generates Lysophosphatidylcholine species containing docosahexaenoic acid (LPC-DHA) which is the predominant form in which DHA is transported across the blood brain barrier, mediated by MajorFacilitator Superfamily Domain Containing 2A (MFSD2a),an LPC-DHA transporter. We found high levels of LPC-DHA in placental tissue and that umbilical vein LPC-DHA levels are higher than maternal circulating concentrations, suggesting that DHA is delivered to the fetus as LPC-DHA. In addition, we discovered that MFSD2a is expressed in the human syncytiotrophoblast basal plasma membrane, consistent with the possibility that this transporter mediates transfer of LPC-DHA to the fetus. These observations provide the premise for our central hypothesis that trophoblast phospholipid synthesis and remodeling are highly active, produces phosphatidic acid (which modulates TOR signaling) and LPC-DHA for transport to the fetus, mediated by MFSD2a. Our hypothesis is supported by compelling preliminary data including evidence that phosphatidic acid regulates placental amino acid transport mediated through mTOR signaling and LPC-DHA is produced in placenta and released to the fetus. We will use human placental tissue, maternal and umbilical blood samples collected from normal and complicated pregnancies, siRNA gene targeting approaches in cultured primary human trophoblast cells incubated in a physiological mixture of 13C-stable isotope labelled fatty acids and trophoblast specific gene targeting in mice to address this hypothesis. These mechanistic placental studies are highly significant because we will use nove approaches to establish that phospholipid synthesis intermediates are important regulators of function and critical mediators of placental transfer of DHA, essential for normal brain development. l

项目摘要 充足的胎盘脂质转移对胎儿的正常生长和大脑发育至关重要， 涉及胎盘脂质处理和转运的机制在很大程度上是未知的。许多重要 妊娠并发症，如宫内生长受限（IUGR）和母体糖尿病， 与胎儿脂肪沉积紊乱相关，可能导致不良的短期和长期 结果。尽管胎盘脂质处理和运输、胎儿脂肪沉积和胎盘脂肪沉积之间存在机械联系， 胎儿大脑发育仍有待确定，新的证据表明，这些怀孕 并发症与胎盘脂质代谢改变有关。合体滋养层， 人胎盘的转运上皮，介导脂质从母体到胎儿的转移 流通现在有令人信服的证据表明，复杂的脂质形式是大量产生的， 合胞体滋养层并可能释放给胎儿。特别是，原代人类滋养层细胞 迅速吸收脂肪酸并将其结合到磷脂中。的从头合成和重塑 磷脂产生一系列生物活性中间体，包括磷脂酸， 调节癌细胞中的mTOR信号传导。磷脂重塑产生溶血磷脂酰胆碱 含有二十二碳六烯酸（LPC-DHA）的物种，所述二十二碳六烯酸是DHA的主要形式， 转运通过血脑屏障，由含有2A的主要促进剂超家族结构域介导 （MFSD 2a），一种LPC-DHA转运蛋白。我们在胎盘组织和脐带组织中发现了高水平的LPC-DHA， 静脉LPC-DHA水平高于母体循环浓度，表明DHA被输送到 胎儿为LPC-DHA。此外，我们发现MFSD 2a在人的乳腺癌中表达， 合体滋养层基底质膜，与这种转运蛋白介导的可能性一致 LPC-DHA转移到胎儿。这些观察为我们的中心假设提供了前提， 滋养层磷脂合成和重塑是高度活跃的，产生磷脂酸（ 调节TOR信号传导）和LPC-DHA用于转运至胎儿，由MFSD 2a介导。我们的假设是 有令人信服的初步数据支持，包括磷脂酸调节胎盘 通过mTOR信号传导介导的氨基酸转运和LPC-DHA在胎盘中产生并释放 对胎儿的影响我们将使用人胎盘组织，母亲和脐带血样本收集从正常 和复杂妊娠，siRNA基因靶向方法在培养的原代人滋养层细胞 在13 C-稳定同位素标记的脂肪酸和滋养层特异性基因的生理混合物中孵育 在小鼠中进行靶向实验来验证这一假设。这些 机械论 胎盘 研究是非常重要的，因为我们将使用新的 方法来建立磷脂合成中间体是重要的调节剂， 功能和关键介质的胎盘转移的DHA，必不可少的正常大脑发育。 L