Gestation Dependent Immune Response to Group B Streptococcus Infection During Pregnancy

项目总结 这个指导临床科学家研究职业发展奖的目标是提供必要的 培训和技能，以发展成为一名成功运行独立研究计划的内科科学家 专注于生殖免疫学。克里斯汀·诺布尔博士是麻省理工学院新生儿科的讲师 范德比尔特大学医学中心。她的职业目标是研究宿主对感染的反应 开发新的诊断和治疗策略，以改善母婴健康。与 C.Henrique Serezani博士、David Aronoff博士和多学科教师监督的强有力的指导 诺布尔博士将掌握系统生物学的技能(包括下一代测序和超高 水平多重免疫荧光)、孕期感染的模拟和生殖技术 免疫学。范德比尔特为科学发现和合作提供了丰富的环境 拥有支持尖端技术的职业发展机会、共享资源和设施 职业生涯早期的内科医生--科学家走上独立之路。 这一建议检验了核心假设，即怀孕期间免疫系统的自然进化 B组链球菌(GBS)感染与妊娠相关的妊娠结局包括 妊娠组织中不同的母婴免疫反应。为了检验这一假设，目标1将 在单细胞水平上定义为响应GBS感染而激活的动态遗传程序 胎龄的作用。宫内妊娠组织具有独特的动态免疫功能 在整个怀孕期间的成分。因此，我们还将使用超高水平的多重免疫荧光 为关键的GBS诱导的免疫反应提供空间背景。先天免疫系统对于 对病原体的保护。宫内壁龛独特地由母体和胎儿组成- 源于天然免疫细胞，包括巨噬细胞。Aim 2将使用独特的鼠标模型来定义 母体和胎儿巨噬细胞对GBS免疫和妊娠结局的不同贡献 在感染之后。这些目标的完成将弥合关于动态性质的实质性知识差距 孕期局部宫内免疫，防止细菌感染。这对于 发现感染的早期诊断指标，但没有这些指标，有必要确定潜在感染 减少GBS感染后不良妊娠结局的治疗机制。

PROJECT SUMMARY The goal of this Mentored Clinical Scientist Research Career Development Award is to provide the necessary training and skills to develop into a physician scientist who successfully runs an independent research program focused on reproductive immunology. Dr. Kristen Noble is an Instructor in the Division of Neonatology at Vanderbilt University Medical Center. Her career goal is to study the host response to infection during pregnancy to develop novel diagnostic and therapeutic strategies to improve maternal-fetal health. With the strong mentorship of Dr. C. Henrique Serezani, Dr. David Aronoff, and a multidisciplinary Faculty Oversight Committee, Dr. Noble will master skills in systems biology (including next generation sequencing and ultra-high level multiplex immunofluorescence), modeling of infection during pregnancy, and techniques in reproductive immunology. Vanderbilt provides a rich environment for scientific discovery and collaboration with unique career development opportunities, shared resources, and facilities with cutting-edge technology to support early career physician-scientists on their path to independence. This proposal tests the central hypothesis that the natural evolution of the immune system during pregnancy dictates gestation-dependent pregnancy outcomes to Group B Streptococcal (GBS) infection, including differential maternal and fetal immune responses in the gestational tissues. To test this hypothesis, Aim 1 will define dynamic genetic programs at the single cell level that are activated in response to GBS infection as a function of gestational age. The intrauterine gestational tissues have unique and dynamic immune compositions throughout pregnancy. Therefore, we will also use ultra-high level multiplex immunofluorescence to provide spatial context to key GBS-induced immune responses. The innate immune system is essential for the protection against pathogens. The intrauterine niche is uniquely composed of both maternal- and fetal- derived innate immune cells, including macrophages. Aim 2 will use unique mouse models to define the differential maternal and fetal macrophage contributions to immunity against GBS and to pregnancy outcomes after infection. Completion of these aims will close substantial knowledge gaps regarding the dynamic nature of local intrauterine immunity protecting against bacterial infection during pregnancy. This is critical for the discovery of early diagnostic indicators of infection of which there are none, and necessary to identify potential therapeutic mechanisms for decreasing poor pregnancy outcomes after GBS infection.