A role for maternal helminth treatment to alter central inflammation and to reduce lifelong offspring inflammation

项目总结 神经炎与一系列疾病有关，包括认知和精神障碍。 健康障碍。治疗和减少神经炎症仍然是医学上的一个挑战。这个 本研究的目的是确定母体蠕虫定植对其新生儿的影响。 和成年后代，特别关注对小胶质细胞功能和炎症的影响 成年期的寿命和海马区依赖行为。正如之前的工作所表明的那样， 新生儿感染通过改变小胶质细胞功能改变神经炎症，并具有持久的， 对成人学习和记忆的负面影响。目前在患有非淋巴疾病的患者群体中的工作 传染性炎症性疾病，如多发性硬化症，表明用 共生寄生虫可能是药物治疗之外的一种新的干预形式。 共栖生物为了生存而发出抗炎信号，这些信号可能 通过减少宿主体内的炎症而具有潜在的好处。先前的研究表明， 母体蠕虫定植可减轻新生儿后代的神经炎症 感染大肠埃希氏菌。同样的研究表明，母体和断奶的结合 子代蠕虫定植挽救海马区依赖背景恐惧的学习缺陷 条件反射任务。需要进一步的研究来了解母体对后代的影响 蠕虫单独定植以及确定影响的持续时间和时间进程 母体蠕虫在我们新生儿感染模型中的定植。这项提议将检验这一假设 仅母体蠕虫的殖民就足以保护后代免受 在整个生命周期内，通过减少海马体内的炎症，可以减少新生儿感染。会的 同时刻画母体蠕虫定植对子代的影响，探讨可能 机制，包括对分离的细胞群体(小胶质细胞、星形胶质细胞和 神经元)来自中枢神经系统。重要的是，该项目建议参与和培训 每年大约有8名本科生在实验室里与啮齿动物一起完成行为任务 分析以及细胞和分子分析技术，如免疫组织化学和 实时定量聚合酶链式反应以及生物信息学项目与下一代RNA测序。这些 研究将阐明母体蠕虫影响的潜在机制，这可以进一步 探索作为对免疫介导性炎症性疾病易感人群的干预措施。

PROJECT SUMMARY Neuroinflammation is correlated with a broad spectrum of disorders, including cognitive and mental health disorders. Treating and reducing neuroinflammation remains a medical challenge. The purpose of this research is to determine the effects of maternal helminth colonization on her neonatal and adult offspring, specifically focused on the effects on microglia function and inflammation across the lifespan as well as hippocampal-dependent behavior in adulthood. As previous work has shown, neonatal infection alters neuroinflammation via changes in microglial function and has an enduring, negative effect on adult learning and memory. Current work in patient populations suffering from non- communicable inflammatory disorders, such as multiple sclerosis, shows that treatment with commensalist parasites may be a new form of intervention beyond pharmaceutical treatments. Commensalist organisms emit anti-inflammatory signals in order to survive, and these signals may have potential benefits by reducing inflammation within their hosts. Previous work has shown that maternal helminth colonization attenuates neuroinflammation in the offspring following a neonatal infection with Escherichia coli. The same work showed that the combination of maternal and weanling offspring helminth colonization rescues learning deficits on a hippocampal-dependent contextual fear conditioning task. Further research is needed to understand the effects on the offspring of maternal helminth colonization alone as well as to define the duration and time course of the effects of maternal helminth colonization in our neonatal infection model. This proposal will test the hypothesis that maternal helminth colonization alone is sufficient to protect offspring from the lifelong effects of neonatal infection by reducing inflammation within the hippocampus throughout the lifespan. It will also characterize the effects of maternal helminth colonization on the offspring to explore possible mechanisms, including mRNA-sequencing of isolated cell populations (microglia, astrocytes and neurons) from the central nervous system. Importantly, this project proposes to engage and train approximately 8 undergraduates working in the lab each year with rodents on behavioral task analysis as well as cellular and molecular analysis techniques, such as immunohistochemistry and real-time quantitative PCR as well as bioinformatics projects with NextGen RNAsequencing. These studies will elucidate potential mechanisms for the effects of maternal helminths that can be further explored as interventions for populations susceptible to immune-mediated inflammatory diseases.