Maternal Obesity, AMPK and Development of Fetal and Neonatal Gut

描述(申请人提供)：孕妇肥胖，AMPK与胎儿和新生儿肠道发育，发育生物学小组，怀俄明大学动物科学系，拉勒米，怀俄明州，82071摘要理性：肥胖，包括孕妇的肥胖，近几十年来迅速增加。与此同时，与肠道相关的疾病的发病率也变得更加常见。母体肥胖与子代肠道相关疾病之间是否存在内在联系？胎儿期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引起肠道炎症的细菌、病毒和大分子的传播，使后代易患炎症性肠道疾病、自身免疫性疾病和食物过敏。无翼和Int(Wnt)/？-catenin信号通路是肠道正常发育和上皮屏障功能所必需的。最近，我们发现AMP激活的蛋白激酶(AMPK)的激活增强了β-连环蛋白的稳定性及其下游信号；同时，我们观察到母亲肥胖抑制了AMPK的活性，并损害了子代肠道上皮屏障功能。中心假说：母体肥胖抑制胎儿肠道AMPK活性，下调β-连环素介导的信号通路，损害子代肠道发育和屏障功能。具体目的：1)评价母体肥胖对AMPK/β-连环蛋白信号转导、子代肠道发育和通透性的影响；2)评估AMPK对胎儿和子代肠道发育和屏障功能的特异性影响。方法：我们计划使用我们成熟的母体肥胖小鼠模型，AMPK亚型特异性条件性基因敲除小鼠，以及体外上皮细胞培养和体外细胞培养进行拟议的研究。目的：研究AMPK在母体肥胖条件下胎儿和新生儿肠道发育及通透性中的作用，并进一步探讨其机制。创新：我们正在进行开创性的研究，以确定AMPK在动物发育中的作用。这项拟议的工作是新颖的，因为AMPK及其相关的信号通路对肠道发育的影响尚未被研究。环境：所需的所有方法均已在PI的实验室建立。该项目的资助将进一步加强我系生物医学研究部分，激发学生对生物医学研究的兴趣，为学生提供实践经验，有利于培养下一代生物医学科学家。影响：拟议的研究将证明AMPK在将母体肥胖与子代肠道发育和通透性联系起来方面发挥关键作用，这将使许多可用的抗糖尿病药物成为可能，AMPK的已知激活剂，可以改善因母体肥胖而受损的子代肠道功能。鉴于肠道屏障功能对健康的重要性，这种干预将有助于这个国家越来越多的肥胖母亲生下健康的孩子。 与公共卫生相关：美国正在经历肥胖症的流行，普通人群和育龄妇女的肥胖率都在上升，而与肠道通透性增强相关的疾病，如自身免疫性疾病、食物过敏和炎症性肠道疾病的发生率也变得更加常见。胎儿肠道发育障碍与成人疾病有关。拟议中的研究将测试母亲肥胖通过AMP激活蛋白激酶(AMPK)损害胎儿肠道发育的概念，这将使使用许多现有的抗糖尿病药物，已知的AMPK激活剂，来改善肥胖母亲的后代肠道功能成为可能。

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.