Metabolic Basis of Disease

项目摘要 美国的大多数成年人超重和/或肥胖。三分之一的成年人患有高血压。 这种心脏代谢流行病的起源可能始于子宫内发育。不良妊娠 结果，如先兆子痫（PE），大大增加了母亲和后代患心脏代谢疾病的风险。 PE定义为妊娠后半期母体高血压和多器官功能障碍。 由于这些体征在胎儿和胎盘娩出后消失，异常的胎儿胎盘单位被认为是 产妇综合症的原因PE母亲所生的后代表现出合并症，包括早产 出生和胎儿生长受限（FGR），这有助于心血管疾病和肥胖的生命周期。 怀孕开始肥胖的妇女发生PE的可能性是正常妇女的3倍。其确切机制是 对后代的长期影响尚不清楚。为了研究PE，我们利用肥胖女性BPH/5 小鼠自发表现出妊娠晚期高血压、胎儿死亡、FGR和妊娠期体重过重 与女性的PE相似。我们的总体假设是，母亲在怀孕早期体重减轻， 可以改变遗传程序并降低女性成人发病心脏代谢疾病的风险 后代成年雌性BPH 5具有加速的追赶性生长和肥胖与瘦素抵抗， 与年龄匹配的瘦型血压正常者相比， 对照小鼠。这些心脏代谢风险因素未反映在BPH/5男性中。妊娠女性BPH/5 妊娠期体重过度增加，妊娠后半期高血压（即叠加PE）， 以及其他新发妊娠合并症，包括脂肪肝。我们的目的是测试BPH/5大坝 从受孕时开始配对喂养，以改善雌性后代的心脏代谢表型风险因素。 初步数据支持我们的方法，即通过在上半年减轻体重来逆转BPH/5产妇肥胖 在该模型中，妊娠的持续时间导致胎儿死亡和FGR的减弱。我们正在进行的COBRE研究是 在BPH/5小鼠中解决母体体重减轻后PE的母体综合征对胎盘发育的影响 该IDEA补充建议检查女性和男性BPH/5后代的性类固醇激素， 以及心脏代谢疾病风险的遗传因素，包括X连锁基因。我们会用黄金 标准液相色谱质谱法用于测量BPH/5小鼠年龄和 X染色体上新的全基因组亚硫酸氢盐测序，以揭示新的遗传扰动， 有助于BPH/5女性中观察到的心脏代谢疾病风险的性别二型性。而且我们 将研究这些标记物的表观遗传和子宫内编程的母亲体重减轻， 心血管疾病这项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.