Placental malaria: The role of inflammation at the maternal-fetal interface

胎盘疟疾：母胎界面炎症的作用

基本信息

批准号：
10306339
负责人：
Stephanie Lina Gaw
金额：
$ 19万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-12-04 至 2023-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10306339
关键词：
Adverse effects Affect Africa South of the Sahara Anemia Antigens Area Award Basement membrane Bioinformatics Biopsy Birth Weight Blood Blood Circulation Blood Vessels Blood specimen California Cells Childhood Chorionic villi Chronic Clinical Complement Data Developing Countries Embryo Equilibrium Erythrocytes Falciparum Malaria Fetal Growth Fetal Growth Retardation Fetus Gene Expression Profiling Genes Goals Gravidity Growth Hormones Human Hypertension Immune Immune response Immunity Immunology Infection Infection Control Inflammation Inflammatory Inflammatory Response Innate Immune Response Interferon Type I Interferon Type II Interferons International Life Cycle Stages Liver Low Birth Weight Infant Malaria Maternal Mortality Maternal-Fetal Exchange Maternal-fetal medicine Mediating Mentors Mesenchymal Modeling Molecular Morbidity - disease rate Mothers Myometrial Nature Nutrient Organ Outcome Parasites Pathologic Pathway interactions Perinatal mortality demographics Placenta Placental Biology Placentation Plasmodium falciparum Play Population Positioning Attribute Pre-Eclampsia Predisposition Pregnancy Pregnancy Complications Pregnancy Histories Pregnancy Outcome Pregnant Women Premature Birth Prevention strategy Process Regulation Research Personnel Resource-limited setting Risk Role Sampling San Francisco Small for Gestational Age Infant Spontaneous abortion Stromal Cells Structure Surface Syncytiotrophoblast Testing Therapeutic Intervention Time Training Trees Uganda Universities Uterus Villous Villus Vulnerable Populations Work angiogenesis cell type cytotrophoblast design differential expression embryo/fetus experimental study fetal genetic signature hormone regulation immunoregulation in vitro Model individual response innovation interstitial laser capture microdissection macrophage malaria infection mortality multidisciplinary neonatal death neonate new therapeutic target perinatal outcomes placental malaria pregnancy disorder professor programs response skills stem cells theories therapeutic target transcriptome transcriptome sequencing translational study transmission process uptake wasting

项目摘要

PROJECT SUMMARY This is an application for a K08 for Dr. Stephanie Gaw Valderramos, an Assistant Professor in Maternal- Fetal Medicine at the University of California at San Francisco who is establishing herself as a young investigator in multidisciplinary translational studies of placental malaria. This award will provide Dr. Valderramos with the support necessary to test the theory that placental malaria causes local inflammatory changes in the placenta, leading to dysregulation of placental function and consequently fetal growth restriction. To achieve this goal, Dr. Valderramos has assembled a mentoring team comprised of Dr. Susan Fisher, an expert in placental biology; Dr. Philip Rosenthal, an international expert in translational studies of malaria; and Dr. Margaret Feeney, an expert in pediatric immune responses to malaria. Little is known about placental development in the setting of malaria, despite fact that maternal infection is responsible for up to 35% of low birth weight infants, and that in high transmission areas, up to 70% of fetal growth restriction cases and 36% of preterm deliveries are attributable to malaria in pregnancy. In placental malaria, P. falciparum-infected red blood cells accumulate in the maternal intervillous spaces of the placenta. It is believed that the inflammatory response to infection underlies the mechanisms by which placental malaria leads to fetal growth restriction; however, the consequences of the differential inflammatory signatures in remain unexplored. Dr. Valderramos’ recent work has shown that maternal and fetal macrophages have distinct gene responses to placental malaria. These differences correlate with birth weight, and depend on the mother’s pregnancy history, suggesting a new explanation for the increased susceptibility to pregnancy complications seen in first-time mothers. She will test the hypothesis that the type I interferon pathway plays an important role regulating the balance between inflammation and immunity in placental malaria, and that more severe dysregulation of this inflammatory response may have a greater negative impact on placental development and pregnancy outcome. Specifically, she will 1) apply a combination of laser capture microdissection and RNAseq approaches to placental biopsies (malaria cases vs. controls) she collected in Uganda, which will enable global transcriptional profiling of immune and other responses of individual placental cell types; and 2) test the effects of differentially expressed molecules that could impact placental development using in vitro models of this process. These studies will identify new targets for therapeutic intervention. Through a focused program of mentored training and coursework, the she will develop advanced skills in placental biology, bioinformatic analysis, translational immunology, and the design and conduct of translational studies of malaria in resource-limited settings. At the completion of this award, Dr. Valderramos will be well positioned to develop an R01 application to further define correlates and mechanisms of pathologic inflammatory responses to placental malaria.

项目概要这是一份 K08 申请，申请者为 Stephanie Gaw Valderramos 博士，她是一名产科助理教授。加州大学旧金山分校胎儿医学专业的年轻女性该奖项将授予胎盘疟疾多学科转化研究的研究员。瓦尔德拉莫斯获得了检验胎盘疟疾导致局部炎症理论所需的支持胎盘的变化，导致胎盘功能失调，从而影响胎儿生长为了实现这一目标，Valderramos 博士组建了一个由 Susan 博士组成的指导团队。 Fisher，胎盘生物学专家；Philip Rosenthal 博士，国际转化研究专家；疟疾；以及儿童疟疾免疫反应专家玛格丽特·菲尼博士目前所知甚少。关于疟疾背景下的胎盘发育，尽管事实上产妇感染是造成疟疾的原因高达 35% 的低出生体重婴儿，而在高传播地区，高达 70% 的胎儿生长限制病例和 36% 的早产可归因于妊娠期疟疾。疟疾、恶性疟原虫感染的红细胞在母体绒毛间隙中积聚据信，对感染的炎症反应是其机制的基础。然而，胎盘疟疾会导致胎儿生长受限；瓦尔德拉莫斯博士最近的研究表明，炎症特征仍未被探索。胎儿巨噬细胞对胎盘疟疾具有不同的基因反应，这些差异与出生相关。体重，并取决于母亲的怀孕史，这对体重增加提出了新的解释她将检验首次母亲对妊娠并发症的易感性。 I型干扰素通路在调节炎症和炎症之间的平衡中发挥重要作用胎盘疟疾中的免疫力，并且这种炎症反应的更严重的失调可能会导致具体来说，她会1）申请。激光捕获显微切割和 RNAseq 方法相结合进行胎盘活检（疟疾她在乌干达收集的病例与对照），这将使免疫和免疫系统的全球转录分析成为可能。个别胎盘细胞类型的其他反应；2) 测试差异表达的影响这些研究将利用这一过程的体外模型来研究可能影响胎盘发育的分子。通过有针对性的指导培训计划确定治疗干预的新目标。通过课程作业，她将培养胎盘生物学、生物信息分析、转化方面的高级技能免疫学，以及在资源有限的环境中设计和开展疟疾转化研究。完成该奖项后，Valderramos 博士将能够开发 R01 应用程序进一步明确胎盘疟疾病理炎症反应的相关性和机制。