Metabolic Basis of Disease

项目摘要 美国大多数成年人超重和/或肥胖。每三个成年人中就有一个患有高血压。 这种心脏代谢流行病的起源可能始于子宫发育。不良妊娠 结果，如先兆子痫(PE)，极大地增加了母亲和子女患心脏代谢性疾病的风险。 PE定义为妊娠期后半期的母体高血压和多器官功能障碍。 由于体征在胎儿和胎盘分娩后消失，异常的胎儿胎盘单位被认为是 产妇综合症的原因。体育母亲所生的孩子表现出包括早产在内的共病 出生和胎儿生长受限(FGR)，导致心血管疾病和肥胖的生命周期。 开始怀孕的肥胖女性患PE的可能性是女性的3倍。其确切的机制是 目前尚不清楚这种病毒对后代的长期影响。为了研究体育，我们利用肥胖的女性BPH/5 小鼠会自发地表现出妊娠晚期高血压、胎儿死亡、FGR和妊娠体重过大。 获得，类似于女性的体育。我们最重要的假设是，孕妇在怀孕早期体重下降 可以改变遗传程序并降低女性成人起病心脏代谢性疾病的风险 后代。成年女性BPH5加速追赶生长和肥胖与瘦素抵抗，增加 血压和孕前雌激素信号改变与年龄匹配的正常血压瘦人相比 控制小鼠。这些心脏代谢危险因素在BPH/5男性中没有反映出来。怀孕女性BPH/5 出现妊娠体重过度增加、妊娠后半期高血压(即叠加PE)、 以及其他新发的妊娠合并症，包括脂肪肝。我们的目标是测试BPH/5大坝 从受孕开始配对喂养以改善雌性后代心脏代谢表型的危险因素。 初步数据支持我们的方法，即在上半年通过减肥来逆转BPH/5母亲肥胖 在该模型中，妊娠的减少导致胎儿死亡和FGR的衰减。我们正在进行的Cobre研究是 BPH/5小鼠减重后母体综合征对胎盘发育的影响 这个想法补充建议检测雌性和雄性BPH/5后代中的性类固醇激素 以及心脏代谢性疾病风险的遗传贡献者，包括X连锁基因。我们会用黄金 标准液相色谱质谱联用法测定BPH/5小鼠年龄和性别激素 X染色体上新的全基因组亚硫酸氢盐测序揭示了新的遗传扰动 导致BPH/5女性心脏代谢性疾病风险的性别二型性。此外，我们 将在这些标志物上调查母亲体重减轻的表观遗传学和宫内编程 心血管疾病。这一建议的发现对于理解PE对后代的影响是必要的 进入成年期，并以性别依赖的方式对母亲肥胖的改善作出反应。

Project Summary The majority of adults in the United States are overweight and/or obese. One in three adults have hypertension. The genesis of this cardiometabolic epidemic likely begins with in utero development. Adverse pregnancy outcomes, such as preeclampsia (PE), greatly increase mother and offspring risk of cardiometabolic diseases. PE is defined as maternal hypertension and multi-organ dysfunction during the second half of pregnancy. Because the signs resolve after delivery of the fetus and placenta, an abnormal fetoplacental unit is regarded as the cause of the maternal syndrome. Offspring born to PE mothers demonstrate co-morbidities, including preterm birth and fetal growth restriction (FGR), which contributes to the cardiovascular disease and obesity lifecycle. Women that begin pregnancy obese are 3 times more likely to develop PE. The precise mechanism of this is unknown and the long-term effects on offspring are unclear. To study PE, we utilize the obese female BPH/5 mice spontaneously exhibit late-gestational hypertension, fetal demise, FGR, and excessive gestational weight gain, similar to PE in women. Our overarching hypothesis is that maternal weight loss in early pregnancy can alter genetic programming and attenuate risk for adult onset cardiometabolic disease in female offspring. Adult female BPH5 have accelerated catch up growth and obesity with leptin resistance, increased blood pressure, and altered estrogen signaling before pregnancy compared to age-matched lean normotensive control mice. These cardiometabolic risk factors are not mirrored in BPH/5 males. Pregnant female BPH/5 develop excessive gestational weight gain, hypertension in the second half of pregnancy (i.e. superimposed PE), and other new onset pregnancy co-morbidities, including fatty liver. Our aims are designed to test BPH/5 dam pair-feeding beginning at conception to improve female offspring cardiometabolic phenotypic risk factors. Preliminary data supports our approach that reversal of BPH/5 maternal obesity via weight loss in the first half of gestation leads to attenuation of fetal demise and FGR in this model. Our ongoing COBRE studies are addressing the maternal syndrome of PE after maternal weight loss on placental development in BPH/5 mice and this IDeA supplement proposes to examine sex steroid hormones in female and male BPH/5 offspring as well as genetic contributors of cardiometabolic disease risk, including X-linked genes. We will use the gold standard liquid chromatography mass spectrometry for measuring sex steroid hormones as BPH/5 mice age and novel whole genome bisulfite sequencing on the X chromosome to reveal novel genetic perturbations that could contribute to the sexual dimorphism of cardiometabolic disease risk seen in BPH/5 females. Furthermore, we will investigate the epigenetic and in utero programming of maternal weight loss on these markers of cardiovascular disease. The findings of this proposal are necessary to understand the effects of PE on offspring into adulthood and their response to improvement of maternal obesity in a sex dependent manner.