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。

基本信息

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
项目类别：
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

项目摘要

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

项目概要充足的脂质胎盘转移对于胎儿的正常生长和大脑发育至关重要，但胎盘脂质处理和运输的机制在很大程度上尚不清楚。许多重要的妊娠并发症，如宫内生长受限 (IUGR) 和孕产妇糖尿病与胎儿脂肪沉积紊乱有关，可能导致短期和长期的不良后果结果。尽管胎盘脂质处理和运输、胎儿脂肪沉积和脂肪之间存在机械联系。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，运输人类胎盘上皮，介导脂质从母体到胎儿的转移循环。现在有令人信服的证据表明复杂的脂质形式是由合体滋养层并可能释放给胎儿。特别是，原代人滋养层细胞快速吸收脂肪酸并将其与磷脂结合。从头合成和重构磷脂产生一系列具有生物活性的中间体，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，这是 DHA 的主要形式由含有 2A 的主要促进子超家族结构域介导穿过血脑屏障 (MFSD2a)，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 MFSD2a 在人类中表达合体滋养层基底质膜，与该转运蛋白介导的可能性一致 LPC-DHA 转移给胎儿。这些观察结果为我们的中心假设提供了前提：滋养层磷脂合成和重塑高度活跃，产生磷脂酸（调节 TOR 信号）和 LPC-DHA，由 MFSD2a 介导转运至胎儿。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的证据通过 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。我们将使用从正常人身上采集的人类胎盘组织、母体和脐血样本和复杂的妊娠，在培养的原代人滋养层细胞中的 siRNA 基因靶向方法在 13C 稳定同位素标记脂肪酸和滋养层特异性基因的生理混合物中孵育以小鼠为目标来解决这一假设。这些机械论的胎盘的研究非常重要，因为我们将使用新的确定磷脂合成中间体是重要调节剂的方法 DHA 胎盘转移的功能和关键介质，对正常大脑发育至关重要。我