Sterol Metabolism During Pregnancy and Development

出生缺陷是导致婴儿出生一年内死亡的主要原因。在美国，三分之一的人 每33个婴儿中就有出生缺陷，包括那些影响身体化学的缺陷(即代谢缺陷)。 尤其是当胆固醇的生物合成受到干扰时，可能会出现毁容缺陷。这条途径产生了一种 质膜的关键结构成分，类固醇激素的前体，并激活声波 Hedgehog，神经元模式的蛋白质关键。受Smith-Lemli-Opitz综合征(SLOS)影响的儿童 有3-羟基类固醇7-还原酶(3-羟基类固醇7-还原酶)缺陷，该酶可转化7-脱氢胆固醇 降至胆固醇。受影响的儿童有低血浆胆固醇浓度，先天性出生缺陷，精神障碍 发育迟缓，无法茁壮成长。根据基因的载频，SLOS是最常见的 常见的先天缺陷。这一缺陷的严重性凸显了胆固醇供应的重要性。 在胎儿发育过程中。最近的人类数据也表明，母体血浆胆固醇可能是 参与调节胎儿生长发育。这对公共健康很重要，因为对妊娠期来说年龄较大 婴儿在成年后患多种疾病的风险增加，包括肥胖和糖尿病。 我们的总体假设是，胆固醇从母体循环到胎儿循环的运输是由 滋养层细胞中分隔两个循环的细胞中的固醇平衡和母体固醇的来源 (胎盘细胞)和内胚层细胞(卵黄囊细胞)。我们将用三个目标来检验我们的假设。1)确定 母体高密度脂蛋白与低密度脂蛋白在将胆固醇输送到胎儿中的重要性。根据初步研究， 我们假设母体高密度脂蛋白-胆固醇优先进入胎儿循环，而低密度脂蛋白-胆固醇优先进入胎儿循环。 优先保留在胎盘和卵黄囊细胞内，以便在激素阴性期间维持基本的细胞 平衡。一旦基本的类固醇需求得到满足，母体的低密度脂蛋白-以及高密度脂蛋白-胆固醇就可以被输送到胎儿。 滋养层细胞系、灌流的人胎盘和啮齿动物卵黄囊将用于这一目的。2)确定 含载脂蛋白E的脂蛋白在向胎儿输送胆固醇中的作用胎盘的含量很高 并能显著地摄取含有载脂蛋白E的脂蛋白。我们假设 含APOE的脂蛋白是胎盘和胎儿的重要来源，一旦是碱性类固醇 滋养层细胞的需求得到了满足。我们将在apoE+/+、apoE-/-和apoE+/-小鼠身上测试我们的假设。3) 描述了调节母体胆固醇向胎儿转移的因素。我们假设这条路线 胎盘的输出(排出/分泌)将受到胆固醇来源--类固醇平衡的影响 (低密度脂蛋白/高密度脂蛋白)和胎儿血浆中的受体。我们将在滋养层细胞系中用不同的 受体(胎儿SLOS高密度脂蛋白)和人类胎盘。从这些研究中收集的数据将有助于形成 在不同条件下促进胎儿发育的新营养策略，或许还有药物策略。

Birth defects are the leading cause of infant death within the first year of life. In the United States, one out of every 33 babies is born with birth defects, including those that affect body chemistry (i.e. metabolic defects). Particularly disfiguring defects can occur when cholesterol biosynthesis is disturbed. This pathway produces a key structural component of plasma membranes, precursors for steroid hormones, and activates sonic hedgehog, a protein key for neuronal patterning. Children affected with Smith-Lemli-Opitz Syndrome (SLOS) have a defect in the enzyme 3-hydroxysteroid 7-reductase (DHCR7), which converts 7-dehydrocholesterol to cholesterol. Affected children have low plasma cholesterol concen-trations, congenital birth defects, mental retardation, and failure to thrive. Based on the carrier frequency of the gene, SLOS is one of the most common congenital defects. The severity of this defect underscores the importance of cholesterol availability in fetal development. Recent data in humans have also suggested that maternal plasma cholesterol may be involved in the regulation of fetal growth. This is important for public health since large-for-gestationally aged infants have an increased risk to develop a number of diseases in adulthood, including obesity and diabetes. Our overall hypothesis is that the transport of cholesterol from the maternal to fetal circulation is regulated by sterol balance and source of maternal sterol in cells which separate the two circulations: trophoblasts (placental cells) and endodermal cells (yolk sac cells). We will test our hypothesis with 3 aims. 1) Determine the importance of maternal HDL vs LDL in delivery of cholesterol to the fetus. Based on preliminary studies, we hypothesize that maternal HDL-CH is preferentially delivered to the fetal circulation while LDL-CH preferentially remains within placental and yolk sac cells for basic cellular maintenance during a negative sterol balance. Once basic sterol needs are met, maternal LDL- as well as HDL-CH can be transported to the fetus. A trophoblast cell line, perfused human placentas, and rodent yolk sacs will be used in this aim. 2) Determine the role of apoE-containing lipoproteins in delivery of cholesterol to the fetus. The placenta has a high content of apoE receptors and can take up apoE-containing lipoproteins at significant rates. We hypothesize that apoE-containing lipoproteins are a substantial source of sterol for the placenta and the fetus once basic sterol needs of trophoblasts are met. We will test our hypothesis in apoE+/+, apoE-/-, and apoE+/- mice. 3) Delineate factors that regulate the transfer of maternal cholesterol to the fetus. We hypothesize that the route of export from the placenta (efflux/secretion) will be affected by sterol balance, source of cholesterol (LDL/HDL), and acceptors in the fetal plasma. We will test this hypothesis in a trophoblast cell line with various acceptors (fetal SLOS HDL) and human placentas. Data gleaned from these studies will help form a basis for new nutritional and perhaps pharmaceutical strategies to enhance fetal development under various conditions.