The impact of maternal S. japonicum infection on fetal metabolism and growth

 描述（由申请人提供）： 胎儿在子宫内所经历的环境对婴儿的成长有重大影响 弹道虽然有流行病学证据表明子宫环境与婴儿早期生长有关，但对母体感染和/或胎盘炎症可能对生长的影响，特别是在幼儿期，仍然缺乏了解。在此，我们的目的是评估母体感染对胎盘营养转运和胎儿代谢激素产生的影响，这是子宫环境受损与儿童早期生长之间的两个潜在机制联系。我们假设这些机制通过降低出生体重和子宫外持续影响导致儿童早期线性生长和营养状况不良。人类血吸虫病感染了2亿人，其中包括4 000万育龄妇女，是寄生虫流行地区发病和死亡的重要原因。我们已经表明，人类中的疟原虫感染导致母胎界面的促炎反应，并可能对受影响后代的出生体重产生不利影响。这一提议是新颖的，因为它能够将子宫内经历的损伤（即使在没有胎盘或胎儿严重感染的情况下）与代谢反应的发展和婴儿生长联系起来。这将通过利用NIH资助的妊娠期间吡喹酮（PZQ）治疗的随机对照试验（RCT）的充分表征的样本和结局以及招募新的孕妇队列来实现。总体研究假设是S.怀孕期间感染日本血吸虫会损害子宫内的营养供应和代谢情况，导致后代生长受限，并使新生儿在随后的生长中处于不利地位。血吸虫病在妊娠初期的潜在影响和对胎儿生长的后果将通过完成三个目标进行严格评估：1）来自妇女的胎盘和脐带血中转运蛋白表达和氨基酸水平的比较± PZQ，2）来自妊娠的婴儿之间6和12个月大时代谢激素谱的比较±PZQ，和3）招募一组新的母婴对，以检查母体血吸虫病以及其他蠕虫感染对代谢谱和两岁以下后代生长的影响。胎盘活检、母亲、婴儿血液和母乳可从RCT获得， 后续Thrasher基金会赠款。此外，对居住在菲律宾同一流行地区的孕妇进行一个新的队列研究，将使整个妊娠期的感染状况与生命头两年的生长特征直接联系起来。创新技术，包括激光捕获显微镜（LCM），定量PCR，反相高效液相色谱法（RP-HPLC），ELISA和胎盘灌注将提供这些研究问题的定量答案。所有三个目标的完成将1）突出血吸虫病背景下子宫内经历的营养缺乏，2）建立在初始损伤期间和进入生命第一年的代谢激素控制改变的先例，和3）以纵向方式评价妊娠期间母体蠕虫感染对胎儿生长的影响，并与妊娠时未并发血吸虫病的妊娠进行直接比较，受孕我在胎盘生物学和分子生物学方面的背景，加上我在全球健康方面的博士后培训，为这项提议奠定了坚实的基础。在四位导师的指导下， 专业知识，以支持我的职业发展，我将应用基本的科学技术和问题，以外地为基础的 全球健康研究，以便为母胎健康领域做出重大和新的贡献。这将通过获得以下三个关键领域的关键新技能来实现：1）进行复杂的海外实地项目，2）流行病学和应用生物统计学，以及3）寄生虫学和生殖生物学。具体来说，我会花大量的钱 在导师的指导下，在实地工作一段时间，收集样本，并启动一项新的基于人口的研究。将通过严格的课程计划、研讨会、国际会议和一对一的培训课程与专门针对其专业领域的导师进行额外培训。拟议的研究经验将使我准备实现我的长期职业目标，成为一个富有成效的，独立的研究者，为母胎健康领域做出有意义的贡献。预计完成拟议的研究将导致额外的赠款提交，包括R 01申请。我受益于一个非常强大的研究环境，我将完成拟议的研究。国际卫生研究中心（CIHR）在培训初级教师在全球卫生成功的独立职业方面有着良好的记录。此外，CIHR与菲律宾热带医学研究所（RITM）之间的杰出合作将使我能够在富有成效的环境中与训练有素的工作人员一起体验海外实地研究的各个方面。罗得岛医院以及妇女和婴儿医院和布朗大学的导师的全力支持将使全球和生殖健康研究成为机构优先事项的研究环境更加完善，并将进一步加强本提案中所述的培训经验。

 DESCRIPTION (provided by applicant): The in utero environment experienced by a fetus can have significant impacts on an infant's growth trajectory. Although there is epidemiological evidence linking the uterine environment and growth in early infancy, there remains a poor understanding of the impact maternal infection and/or placental inflammation may have on growth, particularly during early childhood. Herein, we aim to evaluate the impact of maternal infection on nutrient transport across the placenta and fetal metabolic hormone production, as two potential mechanistic links between a compromised uterine environment and subsequent growth during early childhood. We hypothesize that these mechanisms contribute to poor linear growth and nutritional status in early childhood both through reduced birth weight and continued influences ex utero. Human schistosomiasis infects 200 million individuals, including 40 million women of childbearing age, and is a significant cause of morbidity and mortality in areas where the parasite is endemic. We have shown that schistosome infection in humans results in a pro-inflammatory response at the maternal-fetal interface, and may have a detrimental impact on birth weight of the affected offspring. This proposal is novel in its ability to link insults experienced in utero, even in the absence of gross infection of the placenta or fetus, to development of metabolic responses and infant growth. This will be achieved by leveraging well characterized samples and outcomes from an NIH funded randomized controlled trial (RCT) of Praziquantel (PZQ) treatment during pregnancy, as well as recruiting a new cohort of pregnant women. The overall research hypothesis is that S. japonicum infection during pregnancy impairs nutrient availability and metabolic profiles in utero, resulting in growth restricted offspring and disadvantaged newborns for subsequent growth. The potential impacts of schistosomiasis during the initial stages of gestation and consequences for fetal growth will be rigorously evaluated through completion of three aims: 1) comparison of transporter expression and amino acid levels in the placenta and cord blood from women ± PZQ, 2) comparison of the metabolic hormone profiles at 6 and 12 months of age between infants from pregnancies ±PZQ, and 3) recruitment of a new cohort of mother-infant pairs to examine the impact of maternal schistosomiasis as well as other helminth infections on metabolic profiles and growth in the offspring up to two years of age. Placental biopsies, maternal, infant blood and maternal milk are available from the RCT and a follow-up Thrasher Foundation grant. In addition, the initiation of a new cohort of pregnant women residing in the same endemic region of the Philippines will allow for direct linkage of infection status throughout gestation and growth characteristics through the first two years of life. Innovative techniques including laser capture microscopy (LCM), quantitative PCR, reversed phase high performance liquid chromatography (RP-HPLC), ELISA, and placental perfusion will provide quantifiable answers to these research questions. Completion of all three aims will 1) highlight nutritional deficiencies experienced in utero in the context of schistosomiasis, 2) establish a precedent for altered metabolic hormonal control during initial insult and into the first year of life, and 3) evaluate the impact of maternal helminth infection during gestation on fetal growth in a longitudinal manner with direct comparison to pregnancies not complicated by schistosomiasis at the time of conception. My background in placental biology and molecular biology, coupled with my postdoctoral training in global health has created a solid foundation for this proposal. Under the tutelage of four mentors providing distinct expertise to support my career development, I will apply basic science techniques and questions to field-based global health research in order to make a significant and novel contribution to the area of maternal-fetal health. This will be accomplished by acquiring critical new skills in the following three key areas: 1) conducting complex overseas field projects, 2) epidemiology and applied biostatistics, and 3) parasitology and reproductive biology. Specifically, I will spend significant time in the field under the guidance of mentors, collecting samples and initiating a new population-based study. Additional training will be obtained through a rigorous plan of coursework, seminars, international meetings and one-on-one training sessions with mentors specific to their areas of expertise. The proposed research experiences will prepare me to achieve my longterm career goal of becoming a productive, independent investigator making meaningful contributions to the field of maternal-fetal health. It is expected that the completion f the proposed studies will lead to additional grant submissions, including an R01 application. I benefit from an exceptionally strong research environment in which I will complete the proposed studies. The Center for International Health Research (CIHR) has an excellent track record in training junior faculty for successful independent careers in global health. In addition, the outstanding, established collaboration between CIHR and the Research Institute of Tropical Medicine (RITM) in the Philippines will allow me to experience all aspects of overseas field studies in a productive environment with highly trained staff. The full support of Rhode Island Hospital, as well as mentors at both Women and Infants Hospital and Brown University will round out a research environment in which both global and reproductive health research are institutional priorities and will further strengthen the training experience delineated in this proposal.