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

胎盘疟疾：母胎界面炎症的作用

• 批准号: 10524011
• 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
• 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/10524011
• 关键词: Adverse effects; Affect; Africa South of the Sahara; Anemia; Antigens; Area; Award; Basement membrane; Bathing; Bioinformatics; Biopsy; Birth Weight; Blood; Blood Vessels; Blood specimen; California; Cells; Childhood; Chorionic villi; Chronic; Circulation; 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; Infection; Infection Control; Inflammation; Inflammatory; Inflammatory Response; Innate Immune Response; Interferon Type I; Interferon Type II; Interferons; International; Invaded; Life Cycle Stages; Liver; Low Birth Weight Infant; Macrophage; 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; Penetration; 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; malaria infection; migration; 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 immunology; translational study; transmission process; uptake; wasting

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.

项目摘要 Stephanie Gaw Valderramos博士的K 08申请表，她是一名产妇助理教授， 她是加州大学旧金山分校弗朗西斯科的胎儿医学博士， 胎盘疟疾多学科转化研究的调查员。该奖项将提供博士。 Valderramos在必要的支持下验证了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，Valderramos博士组建了一个由Susan博士 Fisher博士，胎盘生物学专家; Philip Rosenthal博士， 疟疾;和玛格丽特·菲尼博士，一位儿科疟疾免疫反应专家。知之甚少 关于胎盘发育在疟疾的背景下，尽管事实上，产妇感染是负责 高达35%的低出生体重婴儿，在高传播地区，高达70%的胎儿生长 怀孕期间的疟疾造成了36%的早产和限制性病例。胎盘 疟疾，恶性疟原虫感染的红细胞积聚在母体绒毛间隙的空间， 胎盘据信，对感染的炎症反应是引起炎症的机制的基础， 胎盘型疟疾导致胎儿生长受限;然而， 炎症信号仍未被探索。Valderramos博士最近的研究表明， 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，并取决于母亲的怀孕史，提出了一个新的解释增加 第一次做母亲的妇女易患妊娠并发症。她将检验一个假设， I型干扰素途径在调节炎症和炎症之间的平衡中起重要作用， 胎盘型疟疾免疫，以及这种炎症反应更严重失调可能 对胎盘发育和妊娠结局的负面影响更大。具体来说，她将1）申请 将激光捕获显微切割和RNAseq方法结合用于胎盘活检（疟疾 病例与对照），这将使免疫和 单个胎盘细胞类型的其他反应;和2）测试差异表达的 这些分子可能会影响胎盘的发育，使用这个过程的体外模型。这些研究将 确定治疗干预的新靶点。通过有针对性的指导培训计划， 课程，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研究。在 完成该合同后，Valderramos博士将能够很好地开发R 01应用程序， 进一步确定胎盘疟疾病理炎症反应的相关性和机制。

项目成果

Vaginal birth after cesarean: Does accuracy of predicted success change from prenatal intake to admission?

• DOI: 10.1016/j.ajogmf.2020.100094
• 发表时间: 2020-05-01
• 期刊: AMERICAN JOURNAL OF OBSTETRICS & GYNECOLOGY MFM
• 影响因子: 6.3
• 作者: Ha, Thoa K.;Rao, Rashmi R.;Gaw, Stephanie L.
• 通讯作者: Gaw, Stephanie L.

Minimal mRNA uptake and inflammatory response to COVID-19 mRNA vaccine exposure in human placental explants.

人类胎盘外植体中对 COVID-19 mRNA 疫苗暴露的最小 mRNA 摄取和炎症反应。

• DOI: 10.1101/2023.02.01.23285349
• 发表时间: 2023
• 期刊: medRxiv : the preprint server for health sciences
• 作者: Gonzalez,Veronica;Li,Lin;Buarpung,Sirirak;Prahl,Mary;Robinson,JoshuaF;Gaw,StephanieL
• 通讯作者: Gaw,StephanieL

Evaluation of transplacental transfer of mRNA vaccine products and functional antibodies during pregnancy and infancy.

• DOI: 10.1038/s41467-022-32188-1
• 发表时间: 2022-07-30
• 期刊: Nature communications
• 影响因子: 16.6

Analysis of placental pathology after COVID-19 by timing and severity of infection.

• DOI: 10.1016/j.ajogmf.2023.100981
• 发表时间: 2023-07
• 期刊: American journal of obstetrics & gynecology MFM
• 影响因子: 6.3

Nirmatrelvir-Ritonavir (Paxlovid) for Mild Coronavirus Disease 2019 (COVID-19) in Pregnancy and Lactation.

Nirmatrelvir-Ritonavir (Paxlovid) 用于治疗妊娠期和哺乳期轻度冠状病毒病 2019 (COVID-19)。

• DOI: 10.1097/aog.0000000000005152
• 发表时间: 2023
• 期刊: Obstetrics and gynecology
• 影响因子: 7.2
• 作者: Lin,ChristineY;Cassidy,AriannaG;Li,Lin;Prahl,MaryK;Golan,Yarden;Gaw,StephanieL
• 通讯作者: Gaw,StephanieL