A Novel Mouse Model of Obesity in Pregnancy

描述(申请人提供)：由于肥胖是包括2型糖尿病(T2 DM)、心血管疾病(CVD)和癌症在内的一系列疾病的主要风险因素，目前的肥胖流行构成了21世纪全球人类健康的最大威胁之一。传统上，遗传和成人生活方式因素被认为是肥胖、2型糖尿病和心血管疾病风险的主要决定因素。最近的流行病学研究表明，早期发育期间的不利影响(特别是改变了胎儿时期的营养供应)增加了成年后罹患疾病的风险。由于几乎三分之二的美国女性现在进入怀孕阶段，要么超重，要么肥胖，临床研究将怀孕期间的肥胖与儿童代谢综合征的发展联系起来，这一研究尤其令人担忧。然而，这一领域取得进展的一个主要障碍是缺乏对肥胖孕妇代谢环境异常与其子女代谢综合征发展之间联系的机制的了解。不幸的是，目前可用的妊娠期肥胖动物模型不能再现人类状况的关键方面。因此，迫切需要一种具有临床相关性的妊娠期肥胖动物模型。为了满足这一需要，我们提交了这份R24提案，目的是彻底描述一种新的孕期肥胖小鼠模型及其与子代代谢综合征发展的联系。在怀孕期间，我们将重点关注母体代谢、胎盘信号和营养物质运输、胎儿生长和代谢(特定目标1)。此外，将对后代进行仔细的表型分析，特别强调后代的生长、身体成分、新陈代谢、心血管功能和寿命(具体目标2)。在假设生成的无偏见策略中，我们将使用尖端发现方法，包括蛋白质组学、转录组表达研究和小转录组(miRNA，snoRNA)测序。此外，我们将利用成熟而先进的方法来评估体内胎盘血流(微球)、经胎盘转运(Flexner技术)、胰岛素敏感性(正常血糖高胰岛素钳夹)和血压(遥测)。这项建议意义重大，因为它解决了对怀孕期间肥胖动物模型的迫切需求，并有望增加我们对成人疾病宫内编程的机械性理解，这可能导致在怀孕期间采取新的干预策略，以防止肥胖、T2 DM、心血管疾病和癌症的发展。

DESCRIPTION (provided by applicant): Because obesity is a major risk factor for a wide array of diseases including type 2 diabetes (T2DM), cardiovascular disease (CVD) and cancer, the current obesity epidemic constitutes one of the greatest threats to global human health in the 21st century. Genetics and adult life style factors have traditionally been regarded as the primary determinants for the risk to develop obesity, T2DM and CVD. More recently epidemiological studies have demonstrated that adverse influences during early development (in particular altered nutrient availability during fetal life) increase the risk to develop diseas in adult life. Because almost two thirds of American women now enter pregnancy either overweight or obese, clinical studies linking obesity in pregnancy to development of the metabolic syndrome in children is particularly alarming. However, a major obstacle for progress in this area is the lack of understanding of the mechanisms linking the abnormal metabolic environment in the obese pregnant woman to the development of metabolic syndrome in her children. Unfortunately, currently available animal models of obesity in pregnancy do not reproduce key aspects of the human condition. There is therefore an urgent need for an animal model of obesity in pregnancy that is clinically relevant. To address this need, we submit this R24 proposal with the objective to thoroughly characterize a new mouse model of obesity in pregnancy and its links to the development of metabolic syndrome in the offspring. In pregnancy, we will focus on maternal metabolism, placental signaling and nutrient transport, fetal growth and metabolism (Specific Aim 1). Furthermore, the offspring will be carefully phenotyped with particular emphasis on offspring growth, body composition, metabolism, cardiovascular function and longevity (Specific Aim 2). In a hypothesis-generating unbiased strategy, we will employ cutting edge discovery approaches including proteomics, transcriptome expression studies and small transcriptomic (miRNA, snoRNA) sequencing. In addition, we will utilize well-established, yet advanced approaches to assess in vivo placental blood flow (microspheres), transplacental transport (Flexner technique), insulin sensitivity (euglycemic hyperinsulinemic clamp), and blood pressure (telemetry). This proposal is significant because it addresses a critical need for an animal model of obesity in pregnancy and it is expected to increase our mechanistic understanding of intrauterine programming of adult disease, which may lead to novel intervention strategies during pregnancy to prevent the development of obesity, T2DM, CVD and cancer.