Maternal Obesity, AMPK and Development of Fetal and Neonatal Gut

母亲肥胖、AMPK 与胎儿和新生儿肠道发育

• 批准号: 8367647
• 负责人: Meijun Zhu
• 金额: --
• 依托单位: UNIVERSITY OF WYOMING
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-11 至 2012-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8367647
• 关键词: 5' -AMP-activated protein kinase; Academy; Adult; Affect; Age; Age-Years; Allergic Disease; American; Animals; Antidiabetic Drugs; Antigens; Asthma; Autoimmune Diseases; Autoimmune Process; Bacteria; Biomedical Research; Catalytic Domain; Cell Culture Techniques; Cell Differentiation process; Cells; Child; Country; Data; Development; Developmental Biology; Diabetes Mellitus; Disease; Disease Association; Elderly; Energy Metabolism; Epidemic; Epithelial; Epithelial Cells; Epithelium; Fetal Development; Food Hypersensitivity; Funding; Gastrointestinal Diseases; General Population; Health; Hypersensitivity; Immune system; Immunology; Impairment; In Vitro; Incidence; Inflammation; Inflammatory Bowel Diseases; Inflammatory disease of the intestine; Institution; Insulin-Dependent Diabetes Mellitus; Intervention; Knockout Mice; Knowledge; Laboratories; Link; Long-Term Effects; Mediating; Mesenchymal; Metformin; Methodology; Mineral Waters; Mothers; Movement; Neonatal; Nutrient; Obese Mice; Obesity; Patients; Permeability; Pharmaceutical Preparations; Play; Predisposing Factor; Pregnancy; Pregnant Women; Prevalence; Protein Isoforms; Proteins; Research Infrastructure; Resources; Role; Science; Signal Pathway; Signal Transduction; Staging; Stream; Stress; Students; Systems Development; Testing; Tissues; Training; United States; United States National Institutes of Health; Universities; Virus; Woman; Work; Wyoming; autoimmune inflammatory bowel disease; biomedical scientist; child bearing; clinical application; experience; fetal; graduate student; improved; interest; mRNA Expression; macromolecule; mouse model; next generation; novel; offspring; statistics; transmission process; undergraduate student

DESCRIPTION (provided by applicant): Maternal Obesity, AMPK and Development of Fetal and Neonatal Gut Meijun Zhu, Developmental Biology Group, Department of Animal Science, University of Wyoming, Laramie, WY 82071 ABSTRACT RATIONAL: Obesity, including obesity of pregnant woman, is increasing rapidly in recent decades. Meanwhile, the incidence of gut related diseases are also becoming much more common. Is there an inherent link between maternal obesity and gut related diseases in offspring? The fetal stage is critical for gut development and can have long-term effects on the health of the offspring gut. Elevated gut permeability allows the transmission of bacteria, viruses, macromolecules causing gut inflammation, pre-disposing offspring to inflammatory bowel diseases, autoimmune diseases and food allergy. Wingless and Int (Wnt)/?-catenin signaling pathway is essential for proper gut development and epithelial barrier function. Very recently, we found that activation of AMP-activated protein kinase (AMPK) enhances ?-catenin stability and its down-stream signaling; meanwhile, we observed that maternal obesity inhibits AMPK activity and impairs offspring gut epithelial barrier function. CENTRAL HYPOTHESIS: Maternal obesity inhibits AMPK activity in fetal gut, which down-regulates ?-catenin mediated signaling pathway and impairs gut development and barrier function in progeny. SPECIFIC AIMS: 1) To evaluate the impact of maternal obesity on AMPK/?-catenin signaling, development and permeability of progeny gut; 2) to assess the isoform- specific effect of AMPK on fetal and offspring gut development and barrier function. APPROACH: We plan to use our well established maternal obese mouse model, AMPK isoform-specific conditional knockout mice, as well as ex vivo epithelium cultures and in vitro cell cultures for proposed studies. OBJECTIVE: To examine the role of AMPK in fetal and neonatal gut development and permeability under maternal obese condition and to further explore the underlying mechanisms. INNOVATION: We are pioneering studies to define the role of AMPK in animal development. The proposed work is novel, because the effects of AMPK and its associated signaling pathways on gut development have not been studied. ENVIRONMENT: All methodologies required have established in the PI's laboratory. The funding of this project will further strengthen biomedical research component in our department, which will stimulate students' interests in biomedical research and provide students with hands-on experience, facilitating the training of next generation biomedical scientists. IMPACT: Proposed studies will demonstrate that AMPK plays a critical role in linking maternal obesity with gut development and permeability in progeny, which will make it possible to use numerous available anti-diabetic drugs, known activators of AMPK, to improve offspring gut function impaired by maternal obesity. Given the importance of gut barrier function in health, such intervention will help the increasing number of obese mothers in this country to deliver healthy children. PUBLIC HEALTH RELEVANCE: The United States is experiencing an obesity epidemic with increasing obesity rates in both general population as well as women of child bearing years, while the diseases associated with enhanced gut permeability, such as incidence of autoimmune diseases, food allergy and inflammatory bowel diseases, are also becoming much more common. Impairment in fetal gut development is linked to adult diseases. Proposed studies will test the notion that maternal obesity impairs fetal gut development via AMP-activated protein kinase (AMPK), which will make it possible to use numerous available anti-diabetic drugs, known activators of AMPK, to improve offspring gut function of obese mothers.

描述（由申请人提供）：孕产妇肥胖，AMPK以及胎儿和新生儿肠道元元朱，发育生物学小组，动物科学系，怀俄明大学动物科学系，WYMIE，LARAMIE，WY 82071，WY 82071摘要理性：包括孕妇的肥胖症，包括孕妇的肥胖症，最近几十年正在增长。同时，肠道相关疾病的发生也变得越来越普遍。后代孕产妇肥胖与肠道相关疾病之间是否存在固有的联系？胎儿阶段对于肠道发展至关重要，可能会对后代肠道的健康产生长期影响。升高的肠道渗透性允许传播细菌，病毒，大分子，引起肠炎，预疾病前后代到炎症性肠病，自身免疫性疾病和食物过敏。无翅和int（Wnt）/？ - catenin信号通路对于适当的肠道发育和上皮屏障功能至关重要。最近，我们发现AMP激活的蛋白激酶（AMPK）的激活增强了吗？ - 卡丁蛋白的稳定性及其下游信号传导。同时，我们观察到母体肥胖会抑制AMPK活性并损害后代肠上皮屏障功能。中央假设：母体肥胖会抑制胎儿肠道中的AMPK活性，该胎儿肠道的活性下调了？ - 卡丁蛋白介导的信号传导途径并损害后代的肠发展和障碍功能。具体目的：1）评估孕产妇肥胖对AMPK/？ - catenin信号传导，发育和渗透性的影响； 2）评估AMPK对胎儿和后代肠发展和屏障功能的同工型特异性作用。方法：我们计划使用我们建立的孕妇肥胖小鼠模型，AMPK同工型特异性有条件敲除小鼠，以及离体上皮培养物和体外细胞培养物进行拟议的研究。目的：检查AMPK在孕产妇肥胖状况下在胎儿和新生儿肠道发展和渗透性中的作用，并进一步探索潜在的机制。创新：我们正在开创研究，以定义AMPK在动物发育中的作用。拟议的工作是新颖的，因为尚未研究AMPK及其相关信号通路对肠道发育的影响。环境：PI实验室中已经建立了所有所需的方法。该项目的资金将进一步加强我们部门的生物医学研究部分，这将激发学生对生物医学研究的兴趣，并为学生提供动手经验，从而促进对下一代生物医学科学家的培训。影响：拟议的研究将表明，AMPK在将母体肥胖与后代的肠道发展与肠道发育和渗透性联系起来中起着至关重要的作用，这将使使用多种可用的抗糖尿病药物（已知的AMPK激活剂）可以改善母体肥胖症损害的后代肠道肠道功能。鉴于肠道障碍在健康中的重要性，这种干预将有助于该国越来越多的肥胖母亲分娩健康的孩子。 公共卫生相关性：美国正在经历肥胖症流行病，普通人群以及儿童承载年的妇女的肥胖率提高，而与增强的肠道渗透性相关的疾病，自身免疫性疾病，食物过敏和炎症性肠疾病的发病率也变得更加普遍。胎儿肠发展的损害与成人疾病有关。拟议的研究将测试通过AMP激活的蛋白激酶（AMPK）损害孕产妇肥胖的观念，这将使使用许多可用的抗糖尿病药物，即已知的AMPK激活剂，以改善肥胖母亲的肠道肠道功能。