A Novel Mouse Model of Obesity in Pregnancy

一种新型妊娠期肥胖小鼠模型

基本信息

批准号：
9067528
负责人：
Thomas Jansson
金额：
$ 76.59万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-05-12 至 2018-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9067528
关键词：
Address Adolescent Adult American Animal Model Animals Anti-Obesity Agents Area Birth Birth Weight Blood Pressure Blood flow Body Composition Cardiovascular Diseases Cardiovascular Physiology Central obesity Child Childhood Clinical Research Development Diabetes Mellitus Diet Disease Early Intervention Early treatment Environment Epidemic Epidemiologic Studies Exposure to Fatty acid glycerol esters Female Fetal Growth Fetal Growth Retardation Genetic Glucose Growth Health High Density Lipoprotein Cholesterol High Fat Diet High birth weight infant Human Human Characteristics Hypertension Hypertriglyceridemia Incidence Infant Inflammatory Institutes Insulin Insulin Resistance Intervention Knowledge Lead Left Leptin Life Life Style Link Lipolysis Longevity Malignant Neoplasms Metabolic Metabolic syndrome Metabolism MicroRNAs Microspheres Modeling Monoclonal Antibody R24 Mothers Mus National Institute of Child Health and Human Development National Institute of Diabetes and Digestive and Kidney Diseases Non-Insulin-Dependent Diabetes Mellitus Nutrient Obesity Overweight Phenotype Pregnancy Pregnant Women Prevalence Proteomics Public Health Research Research Project Grants Resources Risk Risk Factors Rodent Serum Sheep Signal Transduction Small Nucleolar RNA Techniques Telemetry Toddler United States National Institutes of Health Visceral Woman Work adiponectin animal model development clinically relevant cytokine design feeding fetal in utero in vivo insulin sensitivity interest mouse model nonhuman primate novel obesity in children offspring prevent programs pup response sedentary lifestyle sugar transcriptome transcriptomics transmission process trend

项目摘要

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.

描述（由申请人提供）：因为肥胖是多种疾病的主要危险因素，包括2型糖尿病（T2DM），心血管疾病（CVD）和癌症，因此目前的肥胖症构成了21世纪对全球人类健康的最大威胁之一。传统上，遗传学和成人生活方式因素被视为发展肥胖，T2DM和CVD风险的主要决定因素。最近，流行病学研究表明，早期发育过程中的不利影响（尤其是胎儿生活期间的营养可用性改变）增加了成人生活中疾病的风险。由于现在将近三分之二的美国妇女在怀孕中超重或肥胖，因此将怀孕的肥胖与儿童代谢综合征的发展联系起来的临床研究尤其令人震惊。但是，该领域进步的主要障碍是缺乏对肥胖孕妇异常代谢环境与她孩子中代谢综合征发展的机制的了解。不幸的是，当前可用的妊娠肥胖动物模型不会再现人类状况的关键方面。因此，迫切需要在怀孕中肥胖的动物模型在临床上相关。为了满足这一需求，我们提交了R24提案，其目的是彻底表征怀孕中肥胖的新老鼠模型及其与后代代谢综合征发展的联系。在怀孕中，我们将专注于孕产妇代谢，胎盘信号和营养运输，胎儿生长和代谢（特定目标1）。此外，后代将仔细表型，特别着重于后代生长，身体成分，代谢，心血管功能和寿命（特定目标2）。在假设生成的公正策略中，我们将采用尖端发现方法，包括蛋白质组学，转录组表达研究和小型转录组（miRNA，SNORNA）测序。此外，我们将利用良好但先进的方法评估体内胎盘血流（微球），移植运输（Flexner Technique），胰岛素敏感性（Euglycemic高胰岛素高血压夹）和血压（遥测）。该提议很重要，因为它解决了怀孕肥胖动物模型的迫切需求，并且有望增加我们对成人疾病宫内的机械理解，这可能会导致怀孕期间新颖的干预策略，以防止肥胖，T2DM，CVD和癌症的发展。