STEROL METABOLISM DURING PREGNANCY AND DEVELOPMENT

描述（改编自申请人摘要）：甾醇的获得 对发育和生长至关重要。 三个潜在 胎儿的固醇来源是从头合成，胆固醇 在其他胎儿组织内合成，转运到胎儿， 母体脂蛋白 如果没有足够的胆固醇， 这些来源，胎儿将无法生存或将发展异常。 因此，在本发明中， 本提案的总体目标是界定 胎儿和其它胎儿组织，如胎盘、卵黄囊和蜕膜， 获得胎儿正常发育所需的脂质。 的第一集合中 研究表明，胎儿仓鼠胆固醇的数量，来源于de 新生合成，来自其他胎儿组织内的合成和来自 将对母体循环进行定量。 此外，脂蛋白样 颗粒在卵黄囊中形成和分泌的过程， 胎儿获得外源性胆固醇，会受到操纵， 参与维持胎儿固醇代谢的代偿机制将 评价：载脂蛋白B（apo B）水平较低的小鼠 将用于这些实验。 在 第二组和第三组研究，孕产妇低密度和高密度 脂蛋白-胆固醇浓度（分别为LDL-C和HDL-C）将 变化以模拟典型西方人群中发现的浓度， 这些浓度差异对胎儿发育的影响 将在喂食不同饮食的仓鼠和具有以下任一种的小鼠中进行评价 正常或低载脂蛋白AI水平。 此外，妊娠诱导 高胆固醇血症，通常发生在第三个三个月将是 在仓鼠体内阻断，以检查胎儿组织如何弥补缺乏的 母亲的LDL-C。 最后，各种脂肪酸将被喂养到怀孕 仓鼠和由此产生的影响，他们对固醇代谢， 将评估胎儿的组织，包括大脑。 这些 研究将是第一个确定有多少胎儿胆固醇来自 来自母体循环的血液与来自另一个胎儿的血液 组织，并将开始阐明细胞过程中所涉及的 在不同的人群中维持胎儿的固醇代谢 血浆LDL-和HDL-C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.