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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

基本信息

批准号：
8581649
负责人：
Meijun Zhu
金额：
$ 41.22万
依托单位：
UNIVERSITY OF IDAHO
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-07-11 至 2016-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8581649
关键词：
Maternal Obesity AMPK Development Fetal

项目摘要

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.

描述（申请人提供）：母亲肥胖、AMPK与胎儿和新生儿肠道发育朱美君，动物科学系发育生物学组，拉勒米，WY 82071摘要：近几十年来，肥胖，包括孕妇肥胖，正在迅速增加。与此同时，肠道相关疾病的发病率也越来越普遍。母亲肥胖与后代肠道相关疾病之间是否存在内在联系？胎儿阶段对肠道发育至关重要，并可能对后代肠道健康产生长期影响。肠道通透性升高会导致细菌、病毒、大分子的传播，导致肠道炎症，使后代易患炎症性肠病、自身免疫性疾病和食物过敏。无翼和Int (Wnt)/？-catenin信号通路对肠道正常发育和上皮屏障功能至关重要。最近，我们发现amp活化蛋白激酶（AMPK）的激活可以增强？-catenin稳定性及其下游信号传导；同时，我们观察到母亲肥胖抑制AMPK活性，损害子代肠道上皮屏障功能。中心假设：母体肥胖抑制胎儿肠道AMPK活性，从而下调？-catenin介导的信号通路并损害后代肠道发育和屏障功能。具体目的：1)评估母亲肥胖对AMPK/？-catenin信号传导、后代肠道发育和通透性；2)评估AMPK对胎儿和子代肠道发育和屏障功能的特异性作用。方法：我们计划使用我们已经建立好的母型肥胖小鼠模型，AMPK亚型特异性条件敲除小鼠，以及体外上皮培养和体外细胞培养进行拟议的研究。目的：探讨AMPK在孕妇肥胖情况下胎儿和新生儿肠道发育和通透性中的作用，并进一步探讨其潜在机制。创新：我们在研究AMPK在动物发育中的作用方面处于领先地位。这项工作是新颖的，因为AMPK及其相关信号通路对肠道发育的影响尚未被研究过。环境：项目负责人的实验室已经建立了所需的所有方法。本项目的资助将进一步加强本系的生物医学研究成分，这将激发学生对生物医学研究的兴趣，并为学生提供实践经验，促进下一代生物医学科学家的培养。影响：拟议的研究将证明AMPK在将母体肥胖与后代肠道发育和通透性联系起来方面起着关键作用，这将使使用许多已知的AMPK激活剂的可用抗糖尿病药物来改善母体肥胖受损的后代肠道功能成为可能。鉴于肠道屏障功能对健康的重要性，这种干预将有助于该国越来越多的肥胖母亲生育健康的孩子。