Microbial translocation, inflammation, and adverse pregnancy outcomes in humans

 描述（由申请人提供）：本K24提案有两个主要目标。首先是为候选人Jennifer Friedman，MD，PhD提供时间，为面向患者的研究（POR）中的初级教师提供指导，解决与孕妇和儿童寄生虫病相关的发病机制。第二个目标是为弗里德曼博士提供时间，通过让她追求与她的职业目标相关的高级课程，进一步促进她自己的职业发展。 布朗大学附属医院提供了来自一系列部门/部门的潜在学员的丰富来源，这些部门/部门有兴趣在全球卫生领域进行POR。部门和机构提供了显着的直接支持初级教师进行POR。此外，尽管还有许多其他培训赠款，但有三个T32奖，两个生物医学研究卓越中心（COBRE）奖和一个T37奖，它们可以专门为在弗里德曼博士感兴趣的研究领域进行POR的初级教师提供资金，例如，被忽视的热带病、传染病发病机制和围产期生物学。 该提案的首要科学目标是推进研究，阐明母胎界面的免疫反应导致子宫内生长不良、早产和新生儿铁不足的机制。受指导者将能够利用在菲律宾莱特进行的大规模NIH资助的妊娠12 - 16周吡喹酮随机对照试验的良好特征样本和结果。试验于2012年12月结束，所有样品均可立即使用。我们将专门研究寄生虫抗原和微生物易位的作用，微生物产物从肠道进入体循环的过程，以及IUGR，早产和新生儿铁不足的发病机制中随之而来的炎症。没有研究评估微生物易位（MT）在人类妊娠疾病的背景下。具体来说，我们将使用这个模型来确定MT和炎症通过哪些途径影响胎盘和新生儿IGF途径和铁转移，以及这最终如何影响胎儿生长和铁禀赋。在菲律宾进行长期随访，作为1）我们与菲律宾的热带医学和研究中心赠款的一部分，2）我们的R 01（PI Kurtis，Co-I Friedman），将在2015-16年招募和跟踪受试者，或3）作为他们自己的全球健康POR项目的一部分，由上述培训赠款支持，并在莱特的一个资金充足的地点进行，菲律宾，PI在那里有着长期和富有成效的合作。因此，她将能够模拟这种合作方法。

 DESCRIPTION (provided by applicant): There are two primary goals of this K24 proposal. The first is to provide time for the candidate, Jennifer Friedman, MD, PhD, to provide mentorship to junior faculty in patient oriented research (POR) addressing mechanisms of morbidity related to parasitic diseases among pregnant women and children. The second goal is to provide time for Dr. Friedman to further her own career development by allowing her to pursue advanced coursework related to her career goals. Brown University affiliated hospitals provide a rich source of potential mentees from a range of Departments/Divisions housing junior faculty interested in conducting POR in global health. The Departments and Institution provide significant direct support for junior faculty conducting POR. addition, although there are numerous other training grants, there are three T32 awards, two Centers for Biomedical Research Excellence (COBRE) awards, and one T37, which could specifically provide funding for junior faculty conducting POR in research areas of interest to Dr. Friedman e.g., neglected tropical diseases, infectious disease pathogenesis, and perinatal biology. The overarching scientific goal of this proposal is to advance studies elucidating mechanisms through which immune responses at the maternal-fetal interface culminate poor growth in utero, prematurity, and newborn iron insufficiency. Mentees will be able to leverage well-characterized samples and outcomes from a large scale, NIH funded randomized controlled trial of Praziquantel given at 12 - 16 weeks gestation in Leyte, The Philippines. The trial ended in December of 2012 and all samples are available for immediate use. We will specifically examine the role of both parasitic antigens and microbial translocation, the process of microbial products from the gut entering the systemic circulation, with consequent inflammation in the pathogenesis of IUGR, prematurity, and newborn iron insufficiency. No studies have evaluated microbial translocation (MT) in the context of human diseases of pregnancy. Specifically, we will use this model to identify pathways through which MT and inflammation in these compartments affect placental and newborn IGF pathways and iron transfer and how this ultimately influences fetal growth and iron endowment Though these scientific aims are provided in great detail to provide an example of the candidate's areas of interest and expertise, mentees will also be involved with direct subject enrollment, assessments, and long term follow up in The Philippines as part of 1) our Tropical Medicine and Research Centers grant with The Philippines, 2) our R01 (PI Kurtis, Co-I Friedman) that will enroll and follow subjects in 2015-16, or 3) as part of their own projects in POR in global health as supported by the aforementioned training grants and conducted at a well-funded site in Leyte, The Philippines, where the PI has had a longstanding and fruitful collaborations. She will therefore be able to model this collaborative approach.