STEROL METABOLISM DURING PREGNANCY AND DEVELOPMENT

描述(摘自申请者的摘要)：获取甾醇 对胎儿的发育和成长是必不可少的。三大潜力 胎儿体内固醇的来源是从头合成、胆固醇。 在其他胎儿组织中合成的，被输送到胎儿和 母体脂蛋白。如果没有所需的胆固醇 这些来源，胎儿将无法存活或发育异常。因此， 这项提案的总体目标是勾勒出 胎儿和其他胎儿组织，如胎盘、卵黄囊和蜕膜， 获取正常胎儿发育所需的脂类。在第一组 研究表明，胚胎仓鼠体内的胆固醇来源于 新星合成，来自其他胎儿组织内的合成和来自 母体循环将被量化。此外，类脂蛋白 卵黄囊中颗粒的形成和分泌，通过这个过程 胎儿获得外源性胆固醇，会被操控 维持胎儿类固醇代谢的代偿机制将 接受评估：与低载脂蛋白B(ApoB)水平的小鼠进行比较 过量产生载脂蛋白B的小鼠将被用于这些实验。在 第二和第三组研究，产妇低密度和高密度 脂蛋白-胆固醇浓度(分别为低密度脂蛋白胆固醇和高密度脂蛋白胆固醇)将 变化以模拟典型西方人口中的浓度，以及 这些浓度的差异对胎儿发育的影响 将在喂食不同饲料的仓鼠和有任何一种饲料的老鼠身上进行评估 载脂蛋白AI正常或低水平。此外，因怀孕而引发的 通常发生在妊娠晚期的高胆固醇血症将是 在仓鼠体内受阻，以检查胎儿组织如何弥补缺乏 母体低密度脂蛋白-C的水平。最后，各种脂肪酸将被喂给孕妇 仓鼠及其对小鼠体内固醇代谢的影响 胎儿的组织，包括大脑，将被评估。这些 研究将首次确定胎儿胆固醇的来源 从母体的循环与来自另一个胎儿的循环 组织，并将开始阐明细胞过程中涉及的 不同性别人群中胎儿体内甾醇代谢的维持 血浆低密度脂蛋白和高密度脂蛋白胆固醇浓度。

DESCRIPTION (Adapted from applicant's abstract): The acquisition of sterol by the fetus is essential for development and growth. Three potential sources of sterol for the fetus are de novo synthesis, cholesterol synthesized within other fetal tissues that is transported to the fetus and maternal lipoproteins. Without the required amount of cholesterol from these sources, the fetus will not survive or will develop abnormally. Thus, the overall aim of this proposal is to delineate the mechanisms by which the fetus and other fetal tissues, such as the placenta, yolk sac and decidua, derive the lipids needed for normal fetal development. In the first set of studies, the amount of fetal hamster cholesterol that originates from de novo synthesis, from synthesis within other fetal tissues and from the maternal circulation will be quantitated. In addition, lipoprotein-like particle formation in and secretion from the yolk sac, the process by which the fetus obtains exogenous cholesterol, will be manipulated and the compensatory mechanisms involved in maintaining fetal sterol metabolism will be evaluated: mice with low levels of apolipoprotein B (apoB) as compared to mice that overproduce apoB will be used for these experiments. In the second and third sets of studies, maternal low and high density lipoprotein-cholesterol concentrations (LDL-C and HDL-C, respectively) will be varied to mimic concentrations found in a typical Western population, and the effects these differences in concentrations have on fetal development will be evaluated in hamsters fed different diets and in mice with either normal or low apolipoprotein AI levels. Additionally, the pregnancy-induced hypercholesterolemia that normally occurs during the third trimester will be blocked in hamsters to examine how the fetal tissues compensate for a lack of maternal LDL-C. Finally, various fatty acids will be fed to pregnant hamsters and the resultant, effect they they have on sterol metabolism in the tissues of the fetus, including the brain, will be evaluated. These studies will be the first to determine how much fetal cholesterol is derived from the maternal circulation versus that originating in the other fetal tissues, and will begin to elucidate the cellular processes involved in the maintenance of sterol metabolism in the fetus in a population with different plasma LDL- and HDL-C concentrations.