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

项目总结 这是一份K08的申请书，申请者是史蒂芬妮·高·瓦尔德拉莫斯博士，她是一名母科助理教授。 加州大学旧金山分校的胎儿医学博士，她年轻时就确立了自己的地位 胎盘疟疾多学科转化性研究的调查员。这一奖项将为Dr. Valderramos和必要的支持，以检验胎盘疟疾导致局部炎症的理论 胎盘的变化，导致胎盘功能失调，从而导致胎儿生长 限制。为了实现这一目标，瓦尔德拉莫斯博士组建了一个由苏珊博士组成的指导团队 菲舍尔，胎盘生物学专家；菲利普·罗森塔尔博士，国际胎盘生物学翻译研究专家 疟疾；以及疟疾儿科免疫反应专家玛格丽特·费尼博士。鲜为人知 关于疟疾背景下的胎盘发育，尽管母亲感染是导致 低出生体重儿高达35%，在高传播区，高达70%的胎儿生长 限产病例和36%的早产可归因于孕期疟疾。在胎盘中 疟疾、恶性疟原虫感染的红细胞聚集在母体绒毛间间隙 胎盘。人们认为，对感染的炎症反应是导致 胎盘疟疾导致胎儿生长受限；然而，这种差异的后果 书中的煽动性特征仍未被发掘。瓦尔德拉莫斯博士最近的研究表明，母体和 胎儿巨噬细胞对胎盘疟疾有不同的基因反应。这些差异与出生有关。 体重，并取决于母亲的孕产史，这对体重增加提出了新的解释 对第一次怀孕母亲的妊娠并发症的易感性。她将检验这一假设，即 I型干扰素途径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，以及这种炎症反应的更严重的失调可能 对胎盘发育和妊娠结局的负面影响更大。具体地说，她会申请 激光捕获显微切割和RNAseq联合应用于胎盘活检(疟疾) 病例与对照)，这将使免疫和免疫的全球转录图谱成为可能。 单个胎盘细胞类型的其他反应；以及2)测试差异表达的效果 使用这一过程的体外模型研究可能影响胎盘发育的分子。这些研究将 确定治疗干预的新靶点。通过有重点的辅导性培训和 课程中，她将发展胎盘生物学、生物信息学分析、翻译 免疫学，以及在资源有限的情况下设计和开展疟疾转化性研究。在… 完成这一奖项后，Valderramos博士将能够很好地开发R01应用程序 进一步明确胎盘疟疾病理性炎症反应的相关因素和机制。

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.