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，导致日后肥胖增加。大多数关于发育编程的研究都比较了喂食低脂肪或高脂肪饮食的雌性动物的后代，以诱导炎症，循环代谢物或肥胖差异的差异，因此难以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编程中的作用。重要的循环抗炎剂是高密度脂蛋白（HDL）。HDL直接或通过其流出胆固醇的能力维持细胞固醇平衡来维持炎症。虽然我们和其他人已经表明，由于载脂蛋白A-I（apoA-I）消融导致HDL水平低的小鼠在怀孕期间有更大的炎症，但没有研究检查母体HDL或apoA-I与发育编程的关联。HDL在胎儿结局中可能发挥的作用变得更加相关，因为HDL最近已被证明在妊娠期间是动态的，亚物种（不同大小的HDL颗粒）和不同大小颗粒的组成发生了巨大变化。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的后代的发育编程。为了检验我们的假设，将不具有apoA-I（KO）或apoA-I（WT）的小鼠喂食饮食以诱导中度炎症，并与相反基因型的雄性交配以产生杂合（Het）后代。由于所有的女性都将被喂养相同的饮食，并有相同的肥胖，我们将关注一个因素的影响，即母体炎症对编程的影响。将在以下两个特定目标中检查暴露于不同母体环境的Het后代。目标1。确定母体HDL和/或apoA-I在后代发育编程中的作用。我们将检查在几个年龄（包括子宫内）喂食炎症诱导饮食的WT或KO母鼠的Het后代的表型。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“拯救”后代表型。目标二。确定母体HDL和/或apoA-I在抗原同种异体妊娠后代发育编程中的作用。同种异体妊娠（不同品系小鼠之间的交配）比同系妊娠更具抗原性，因为它导致胎儿组织在遗传上与妊娠雌性不同，并且需要最佳功能的免疫细胞。我们将研究C57 BL/6雌性与相反基因型的BALB/c雄性交配的Het后代，并检查后代表型。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-I，重组HDL或其下游靶点来改善后代在其生命周期中的健康。

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.