Sterol Metabolism During Pregnancy and Development

怀孕和发育期间的甾醇代谢

• 批准号: 7675080
• 负责人: LAURA A WOOLLETT
• 金额: $ 29.84万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-01 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7675080
• 关键词: 7-dehydrocholesterol; Affect; Age; Apolipoprotein E; Birth Weight; Blood Circulation; Cell Line; Cell membrane; Cell physiology; Cells; Cessation of life; Chemistry; Child; Cholesterol; Cholesterol Homeostasis; Condition; Congenital Abnormality; Data; Defect; Development; Diabetes Mellitus; Disease; Endoderm Cell; Enzymes; Equilibrium; Erinaceidae; Failure to Thrive; Fetal Development; Fetal Growth; Fetus; Gene Frequency; Glean; Goals; Growth; High Density Lipoprotein Cholesterol; High Density Lipoproteins; Human; Human Cell Line; Hydroxysteroids; Infant; Inherited; LDL Cholesterol Lipoproteins; LDL-Receptor Related Protein 1; Laboratories; Life; Lipoprotein (a); Lipoprotein (a-); Lipoproteins; Low-Density Lipoproteins; Maintenance; Mental Retardation; Metabolic; Metabolism; Mothers; Mus; Neurons; Newborn Infant; Numbers; Nutritional; Obesity; Oxidoreductase; Pathway interactions; Pattern; Perfusion; Pharmacologic Substance; Placenta; Plasma; Play; Pregnancy; Pregnant Women; Proteins; Public Health; Rate; Regulation; Risk; Rodent; Role; Route; Serum; Severities; Smith-Lemli-Opitz Syndrome; Source; Sterols; Testing; United States; Work; Yolk Sac; aged; base; cholesterol biosynthesis; fetal; lipoprotein cholesterol; receptor; steroid hormone; trophoblast

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.

出生缺陷是婴儿出生后第一年内死亡的主要原因。在美国， 每33名婴儿出生时就有先天缺陷，包括影响身体化学的缺陷（即代谢缺陷）。 当胆固醇生物合成受到干扰时，会发生特别的毁容缺陷。这条途径产生一种 质膜的关键结构成分，类固醇激素的前体，并激活声波 hedgehog，神经元模式的关键蛋白质。Smith-Lemli-Opitz综合征（SLOS） 在酶3中有缺陷- 羟基类固醇 7-还原酶（DHCR 7），其转化7-脱氢胆固醇 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 发育迟缓，无法茁壮成长。根据该基因的携带频率，SLOS是最常见的 常见的先天性缺陷这种缺陷的严重性强调了胆固醇可用性的重要性 在胎儿发育中。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。这对公共卫生很重要，因为妊娠期大 婴儿在成年后患上包括肥胖症和糖尿病在内的多种疾病的风险增加。 我们的总体假设是，胆固醇从母体循环到胎儿循环的转运是由 分离两个循环的细胞中的甾醇平衡和母体甾醇的来源：滋养层 （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向胎儿输送胆固醇方面的重要性。根据初步研究， 我们假设母体HDL-CH优先输送到胎儿循环，而LDL-CH 在固醇阴性时，优先保留在胎盘和卵黄囊细胞内，用于基本的细胞维持 平衡一旦基本的固醇需求得到满足，母体LDL-以及HDL-CH可以运输到胎儿。 滋养层细胞系，灌注的人胎盘，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。胎盘中含有大量的 apoE受体，并能以显著的速率摄取含apoE的脂蛋白。我们假设 含apoE的脂蛋白是胎盘和胎儿的主要甾醇来源， 滋养层的需要得到满足。我们将在apoE+/+、apoE-/-和apoE+/-小鼠中检验我们的假设。第三章 描述调节母体胆固醇向胎儿转移的因素。我们假设这条路线 从胎盘的输出（流出/分泌）将受到固醇平衡的影响，胆固醇的来源 (LDL/HDL）和胎儿血浆中的受体。我们将在滋养层细胞系中测试这一假设， 受体（胎儿SLOS HDL）和人胎盘。从这些研究中收集的数据将有助于为以下方面奠定基础： 新的营养和药物策略，以促进胎儿在各种条件下的发育。