A Novel Mouse Model of Obesity in Pregnancy

描述（由申请人提供）：由于肥胖是包括2型糖尿病（T2DM）、心血管疾病（CVD）和癌症在内的多种疾病的主要风险因素，因此当前的肥胖流行构成了21世纪世纪全球人类健康的最大威胁之一。遗传和成人生活方式因素传统上被认为是肥胖、T2DM和CVD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（特别是胎儿期营养供应的改变）增加了成年后患病的风险。由于近三分之二的美国妇女现在进入怀孕超重或肥胖，临床研究连接肥胖在怀孕期间发展的代谢综合征的儿童是特别令人震惊的。然而，该领域取得进展的一个主要障碍是对肥胖孕妇异常代谢环境与其孩子代谢综合征发展之间的机制缺乏了解。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，迫切需要一种临床相关的妊娠期肥胖动物模型。为了满足这一需求，我们提交了这个R24提案，目的是彻底描述一种新的妊娠期肥胖小鼠模型及其与后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、胎盘信号传导和营养转运、胎儿生长和代谢（具体目标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、身体组成、代谢、心血管功能和寿命（具体目标2）。在一个假设产生无偏的策略，我们将采用尖端的发现方法，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，我们将利用成熟但先进的方法评估体内胎盘血流量（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）。这一提议意义重大，因为它解决了对妊娠期肥胖动物模型的迫切需求，预计将增加我们对成人疾病宫内编程的机械理解，这可能导致妊娠期新的干预策略，以预防肥胖，T2DM，CVD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.