Maternal Obesity, AMPK and Development of Fetal and Neonatal Gut

描述（由申请人提供）：母体肥胖、AMPK和胎儿及新生儿肠道发育Meijun Zhu，发育生物学组，动物科学系，怀俄明州大学，拉勒米，怀俄明州82071摘要：近几十年来，肥胖症，包括孕妇肥胖症正在迅速增加。与此同时，肠道相关疾病的发病率也变得越来越普遍。母亲肥胖和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，并可能对后代肠道的健康产生长期影响。肠道通透性升高允许细菌、病毒、大分子的传播，引起肠道炎症，使后代易患炎症性肠病、自身免疫性疾病和食物过敏。Wingless和Int（Wnt）/？-连环蛋白信号通路对于适当的肠道发育和上皮屏障功能是必需的。最近，我们发现AMP激活蛋白激酶（AMPK）的激活增强了？连环蛋白稳定性及其下游信号传导;同时，我们观察到母体肥胖抑制AMPK活性并损害后代肠道上皮屏障功能。中枢假设：母体肥胖抑制了胎儿肠道中AMPK的活性，从而下调了？连环蛋白介导的信号传导途径并损害后代的肠道发育和屏障功能。具体目的：1）评价母亲肥胖对AMPK/β-内酰胺酶的影响。连环蛋白信号传导、后代肠道的发育和渗透性; 2）评估AMPK对胎儿和后代肠道发育和屏障功能的同种型特异性作用。方法：我们计划使用我们完善的母体肥胖小鼠模型，AMPK亚型特异性条件性敲除小鼠，以及离体上皮细胞培养物和体外细胞培养物进行拟议的研究。目的：探讨AMPK在肥胖孕妇胎儿和新生儿肠道发育和通透性中的作用及其机制。创新：我们正在开拓研究，以确定AMPK在动物发育中的作用。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研究。环境：PI实验室已建立了所需的所有方法。该项目的资助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，并为学生提供实践经验，促进下一代生物医学科学家的培训。影响：提出的研究将证明AMPK在将母体肥胖与后代的肠道发育和渗透性联系起来方面起着关键作用，这将使得有可能使用许多可用的抗糖尿病药物（已知的AMPK激活剂）来改善因母体肥胖而受损的后代肠道功能。鉴于肠道屏障功能在健康中的重要性，这种干预将有助于该国越来越多的肥胖母亲生下健康的孩子。

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.