The role of HDL in developmental programming

宫内环境可能会对后代产生长期的影响。事实上，生长速度改变或暴露在各种应激源下的胎儿可以重新编程，通常会促进新陈代谢变化，导致日后肥胖增加。大多数关于发育规划的研究都比较了喂食低脂或高脂饮食的雌性动物的后代，以导致炎症、循环代谢物或肥胖方面的差异，这使得确定负责规划的关键变量(S)变得困难。这里提出的研究将直接调查母体炎症的作用，独立于饮食因素和母体肥胖，以及主要的先天抗炎途径在发育规划中的作用。重要的循环抗炎药是高密度脂蛋白(HDL)。高密度脂蛋白直接或通过其排出胆固醇的能力维持细胞内的类固醇平衡来维持炎症。尽管我们和其他人已经证明，由于去掉载脂蛋白A-I(apoA-I)而导致高密度脂蛋白水平低的小鼠在怀孕期间有更严重的炎症，但还没有研究检验母体高密度脂蛋白或载脂蛋白A-I与发育规划的关系。高密度脂蛋白在胎儿结局中可能发挥的作用变得更加相关，因为高密度脂蛋白最近被证明在怀孕期间是动态的，在亚种形成(不同大小的高密度脂蛋白颗粒)和不同大小颗粒的组成方面发生了戏剧性的变化。因此，我们假设，母体高密度脂蛋白和/或载脂蛋白A-I通过减轻胎儿炎症，改善了喂养炎症诱导饮食的雌性后代的发育规划。为了验证我们的假设，没有apoA-I(KO)或apoA-I(WT)的小鼠将被喂以诱导中度炎症的饮食，并与相反基因的雄性交配以产生杂合子(Het)后代。由于所有女性都将得到相同的饮食和相同的肥胖症，我们将关注一个因素对编程的影响，即母体炎症。Het后代暴露在不同的母体环境中，将在以下两个特定目标下进行检查。目的1.确定母体高密度脂蛋白和/或载脂蛋白A-I在子代发育规划中的作用。我们将检查来自WT或KO母猪的Het后代的表型，这些后代在几个年龄段饲喂致炎饲料，包括在子宫内。我们将尝试通过饮食白藜芦醇阻断母体炎症和胎儿炎症来“挽救”后代的表型。目的2.确定母体高密度脂蛋白和/或载脂蛋白A-I在抗原性异基因妊娠后代发育规划中的作用。异基因妊娠(不同品系的小鼠之间的交配)比同基因妊娠更具抗原性，因为它产生的胎儿组织在基因上与怀孕的雌性不同，需要最佳功能的免疫细胞。我们将研究C57BL/6雌性与BALB/c雄性交配的Het后代，所检测的后代表型与C57BL/6相反。我们的研究是有影响的，因为我们的结果可能开辟一个新的治疗领域，专注于使用apoA-I、重组高密度脂蛋白或其下游靶标来改善后代一生中的健康。

The in utero environment can have long-lasting consequences to the offspring. Indeed, fetuses with modified growth rates or exposed to a variety of stressors can be re-programmed, often promoting metabolic changes that lead to increased adiposity later in life. Most of the studies on developmental programming have compared offspring of females fed low or high fat diets to induce differences in inflammation, circulating metabolites, or differences in adiposity, making it difficult to determine the key variable(s) responsible for programming. The studies proposed here will directly investigate the role of maternal inflammation, independent of dietary factors and maternal adiposity, and the role of major innate anti-inflammatory pathways in developmental programming. Important circulating anti-inflammatory agents are high density lipoproteins (HDL). HDL maintains inflammation either directly or through maintenance of cellular sterol balance via its ability to efflux cholesterol. Though we and others have shown that mice with low HDL levels due to apolipoprotein A-I (apoA-I) ablation have greater inflammation during pregnancy, no studies have examined an association of maternal HDL or apoA-I with developmental programming. The role that HDL may play in fetal outcomes has become more relevant as HDL has recently been shown to be dynamic during pregnancy, with dramatic changes occurring in subspeciation (different-sized HDL particles) and compositions of the different-sized particles. Thus, we hypothesize that maternal HDL and/or apoA-I improves developmental programming of offspring of females fed an inflammation- inducing diet by mitigating fetal inflammation. To test our hypothesis, mice with no apoA-I (KO) or apoA-I (WT) will be fed a diet to induce moderate inflammation and mated with males of the opposite genotype to generate heterozygous (Het) offspring. As all females will be fed the same diet and have the same adiposity, we will be looking at the impact of one factor, that being maternal inflammation, on programming. The Het offspring, exposed to different maternal milieu, will be examined in the following two specific aims. Aim 1. Determine the role of maternal HDL and/or apoA-I in developmental programming of offspring. We will examine the phenotype of Het offspring from WT or KO dams fed inflammation-inducing diets at several ages, including in utero. We will attempt to “rescue” the offspring phenotype by blocking maternal inflammation and fetal inflammation with dietary resveratrol. Aim 2. Determine the role of maternal HDL and/or apoA-I in developmental programming of offspring from an antigenic allogeneic pregnancy. An allogeneic pregnancy (matings between mice of different strains) is more antigenic than syngeneic pregnancy as it results in fetal tissues that are genetically dissimilar from the pregnant female and requires optimally functioning immune cells. We will study Het offspring from C57BL/6 females mated to BALB/c males of the opposite genotype and offspring phenotype examined. Our studies are impactful as our results could open up a new area of treatments focusing on the use of apoA-I, recombinant HDL, or their downstream targets to improve the health of offspring during their lifespan.