The role of HDL in developmental programming

子宫内的环境会对后代产生长期的影响。事实上，生长速度改变或暴露于各种压力源的胎儿可以被重新编程，通常会促进代谢变化，导致以后的肥胖增加。大多数关于发育编程的研究都比较了喂食低脂或高脂饮食的雌性后代，以诱导炎症、循环代谢物或肥胖的差异，因此很难确定负责编程的关键变量。本文提出的研究将直接研究母体炎症的作用，独立于饮食因素和母体肥胖，以及主要先天抗炎途径在发育规划中的作用。重要的循环抗炎剂是高密度脂蛋白（HDL）。HDL可以直接维持炎症，也可以通过其排出胆固醇的能力来维持细胞固醇平衡。虽然我们和其他人已经证明，由于载脂蛋白A-I （apoA-I）消融导致高密度脂蛋白水平降低的小鼠在怀孕期间有更大的炎症，但没有研究检查母体高密度脂蛋白或apoA-I与发育程序的关联。高密度脂蛋白在胎儿结局中可能发挥的作用已经变得更加相关，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（不同大小的高密度脂蛋白颗粒）和不同大小颗粒的组成中发生了巨大的变化。因此，我们假设母体HDL和/或apoA-I通过减轻胎儿炎症来改善喂食炎症诱导饮食的雌性后代的发育程序。为了验证我们的假设，没有apoa - 1 （KO）或apoa - 1 （WT）的小鼠将被喂食引起中度炎症的饮食，并与相反基因型的雄性交配以产生杂合（Het）后代。由于所有的雌性都将被喂食相同的饮食和相同的肥胖，我们将研究一个因素的影响，即母体炎症，对编程的影响。暴露在不同母系环境中的Het后代将在以下两个具体目标中进行研究。目的1。确定母体HDL和/或apoa - 1在后代发育规划中的作用。我们将研究WT或KO母鼠在不同年龄（包括在子宫内）饲喂炎症诱导饮食的Het后代的表型。我们将尝试通过膳食白藜芦醇阻断母体炎症和胎儿炎症来“拯救”后代表型。目标2。确定母体HDL和/或apoA-I在抗原异基因妊娠后代发育规划中的作用。异体妊娠（不同品系的小鼠之间的交配）比同基因妊娠更具抗原性，因为它会导致胎儿组织在基因上与怀孕的雌性不同，并且需要最佳功能的免疫细胞。我们将研究C57BL/6雌性与相反基因型的BALB/c雄性交配的Het后代，并检测后代表型。我们的研究是有影响力的，因为我们的结果可以开辟一个新的治疗领域，重点是使用apoa - 1，重组HDL或它们的下游靶点来改善后代的健康。

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.