Infectious Events in Pregnancy: PlGF Contributes to Maternal Morbidity

妊娠期感染事件：PLGF 导致孕产妇发病

• 批准号: 9563311
• 负责人: Laura F Newell
• 金额: $ 15.86万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-11 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9563311
• 关键词: Adult; Agonist; Automobile Driving; Basic Science; Bioinformatics; Biometry; CD14 gene; Cells; Cessation of life; Clinical; Critical Illness; Cytokine Gene; Data; Development; Development Plans; Discipline of obstetrics; Disease; Distal; Enhancers; Ensure; Environment; Event; Extramural Activities; Feedback; Fetal health; Fetus; Functional disorder; Funding; Gene Activation; Gene Expression; Genes; Genetic Transcription; Goals; Grant; Gynecology; Hematology; Immune; Immune response; In Vitro; Incidence; Infection; Inflammatory; Inflammatory Response; Influenza A Virus, H1N1 Subtype; Innate Immune System; Institution; International; Knowledge; Lead; Manuscripts; Maternal Health; Maternal-fetal medicine; Mediating; Mentors; Mentorship; Methods; Molecular; Molecular Biology; Mononuclear; Morbidity - disease rate; Mothers; NF-kappa B; Outcome; Pathogenesis; Pathologic; Pathway interactions; Phagocytes; Pharmacology; Physicians; Placental Biology; Placental Growth Factor; Pregnancy; Pregnancy Complications; Pregnancy Trimesters; Pregnant Women; Prevention strategy; Production; Promoter Regions; Receptor Activation; Research; Research Personnel; Risk; Role; Scientist; Signal Pathway; Signal Transduction; Stimulus; TNF gene; Third Pregnancy Trimester; Toll-Like Receptor Pathway; Toll-like receptors; Training; Transcript; Translating; Translational Research; Woman; career development; cytokine; design; enhancing factor; fetal; genetic signature; high risk; immune activation; improved; in vivo; inflammatory milieu; interest; macrophage; maternal morbidity; monocyte; mortality; multidisciplinary; novel; pandemic influenza; programs; research and development; research study; response; skills; small molecule inhibitor; symposium; translational research program; treatment strategy; trophoblast

PROJECT SUMMARY / ABSTRACT During pregnancy, women are at an increased risk of infectious complications, leading to potentially devastating effects on both maternal and fetal morbidity and mortality. The 2009 H1N1 influenza pandemic was a notable example, in which pregnancy was associated with an 8-fold increased risk of death among adults with H1N1, with the highest incidence of death in pregnant women occurring in the 3rd trimester. Levels of placental growth factor (PlGF) increase during normal 3rd trimester of pregnancy, correlating with this period of highest risk for infectious complications. Our hypothesis is that PlGF contributes to an exaggerated, pathologic pro-inflammatory state in response to toll-like receptor (TLR) pathway activation, directly contributing to maternal and fetal morbidity and mortality in the setting of infectious complications. Our preliminary data support our hypothesis, and we have determined that PlGF significantly enhances TLR-mediated inflammatory cytokine production by primary mononuclear phagocytes, modulating cytokine gene transcription via activation of the TLR-pathway. The objectives of this study are to define molecular mechanisms of this `PlGF/TLR' effect, and to determine the contribution of the trophoblast and fetal macrophages to this inflammatory response, with an ultimate goal of developing targeted pharmacological therapies specifically for women critically-ill with infection-mediated inflammatory complications during pregnancy. We have 3 specific aims: Aim 1 is designed to identify molecular determinants contributing to PlGF-mediated TLR-pathway hyper-reactivity in primary monocytes, Aim 2 seeks to determine mechanisms by which placental trophoblasts and macrophages enhance TLR-mediated inflammatory signaling, Aim 3 is designed to determine the effect of in vivo PlGF priming during pregnancy on TLR- activation of maternal monocytes. The training objective of this proposal is to achieve independence as a physician- scientist with expertise in 1) placental biology 2) the role of the trophoblast in driving inflammatory complications, and 3) intrinsic regulators of TLR-pathway activation. This proposed research is part of a personalized 4-year training and career development research program for the applicant. The applicant is well-suited to perform the studies proposed in this application, given her preliminary studies on the PlGF/TLR effect in circulating mononuclear phagocytes, and her multi-disciplinary and cross-institutional mentorship committee involving the fields of Hematology, Molecular Biology and Cell Signaling, Gene Profiling and Bioinformatics, Obstetrics/ Gynecology and Maternal Fetal Medicine, and Placental Biology. Her lead mentor is an extramurally funded, internationally recognized scientist with expertise in Placental Origins of Disease. Moreover, the environment at the applicant's institution is uniquely situated to ensure the successful completion of the aims of this proposal, as an internationally recognized center of expertise in placental biology and placental origins of disease, and the institution is fully committed to the applicant's long-term career development. This translational research will have a significant impact on the field of maternal-fetal medicine, by determining mechanisms involved in the increased vulnerability during pregnancy to severe infectious and inflammatory complications, pathways that can potentially be targeted in pregnant women critically ill with infection-mediated inflammatory complications.

项目摘要 /摘要 在怀孕期间，妇女患感染性并发症的风险增加，导致潜在的毁灭性影响 在孕产妇的发病率和死亡率上。 2009年H1N1流感大流行是一个显着的例子， 哪种妊娠与H1N1成年人的死亡风险增加了8倍，最高 孕妇发生死亡的发生率在三个月发生。胎盘生长因子（PLGF）的水平增加 在正常的三个孕期期间，与感染并发症风险最高的时​​期相关。我们的 假设是，PLGF响应Toll样受体有助于夸张的病理性促炎状态 （TLR）途径激活，直接导致母体和胎儿的发病率和死亡率 并发症。我们的初步数据支持我们的假设，我们已经确定PLGF显着增强 原代单核吞噬细胞产生TLR介导的炎症细胞因子，调节细胞因子基因 通过激活TLR-Pathway的转录。这项研究的目的是定义该研究的分子机制 “ PLGF/TLR”效应，并确定滋养细胞和胎儿巨噬细胞对这种炎症的贡献 反应，其最终目的是开发针对妇女至关重要的靶向药理学疗法 感染介导的炎症并发症在怀孕期间。我们有3个具体目标：AIM 1旨在 鉴定有助于PLGF介导的TLR-Pathway的分子决定因素，在原代单核细胞中，AIM 2试图确定胎盘滋养细胞和巨噬细胞增强TLR介导的机制 炎症信号传导，AIM 3旨在确定妊娠期间体内PLGF启动对TLR-的影响 母体单核细胞的激活。该提案的培训目标是作为医生实现独立性 - 具有专业知识的科学家1）胎盘生物学2）滋养细胞在驱动炎症并发症和 3）TLR-Pathway激活的内在调节剂。这项拟议的研究是一个个性化的4年培训的一部分， 申请人的职业发展研究计划。申请人非常适合进行提出的研究 考虑到她对循环单核吞噬细胞中PLGF/TLR效应的初步研究，她 涉及血液学领域，分子生物学领域的多学科和跨机构指导委员会 以及细胞信号，基因分析和生物信息学，妇产科和母体胎儿医学以及胎盘 生物学。她的主导导师是一位具有外部资助的国际认可的科学家，具有胎盘专业知识 疾病的起源。此外，申请人机构的环境具有独特的位置，以确保成功 完成该提案的目标，作为国际认可的胎盘生物学专业知识中心和 疾病的胎盘起源，该机构完全致力于申请人的长期职业发展。这 转化研究将通过确定机制来对母亲 - 狂热医学领域产生重大影响 涉及怀孕期间对严重感染和炎症并发症的脆弱性，途径 这种可能是针对感染介导的炎症并发症患孕妇重病的孕妇。