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

母体寄生虫治疗在改变中枢炎症和减少后代终生炎症方面的作用

• 批准号: 10579521
• 负责人: Lauren L Williamson
• 金额: $ 40.07万
• 依托单位: NORTHERN KENTUCKY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-20 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10579521
• 关键词: ARHGEF5 gene; Academic Research Enhancement Awards; Acute; Adolescence; Adult; Adult Children; Adverse event; Affect; Animal Model; Anti-Inflammatory Agents; Antiinflammatory Effect; Anxiety; Astrocytes; Attenuated; Autoimmune Diseases; Bacterial Infections; Behavior; Behavioral; Behavioral Paradigm; Bioinformatics; Biological Models; Blood Circulation; Brain; Cell Communication; Cell Separation; Cells; Chronic; Cognition; Cognition Disorders; Cognitive; Cognitive deficits; Conceptions; Disease; Elderly; Encephalitis; Escherichia coli; Escherichia coli Infections; Female; Gene Expression; Genes; Genetic; Goals; Health; Helminths; Hippocampus (Brain); Hour; Human; Immune; Immune response; Immunohistochemistry; Impaired cognition; Infant; Infection; Inflammation; Inflammatory; Intervention; Laboratories; Learning; Life; Longevity; Measures; Mediating; Medical; Memory; Memory impairment; Mental Depression; Mental disorders; Microglia; Microspheres; Modeling; Molecular; Molecular Analysis; Mothers; Multiple Sclerosis; Neonatal; Neuraxis; Neuroimmune; Neurons; Newborn Infant; Organism; Outcome; Parasites; Pathway interactions; Peripheral; Pharmacologic Substance; Physiological; Population; Population Intervention; Psychoneuroimmunology; RNA; Rattus; Research; Rodent; Role; Signal Transduction; Symptoms; Techniques; Testing; Time; Tissues; Training; Work; autism spectrum disorder; cell type; cognitive performance; conditioned fear; cytokine; fascinate; mRNA sequencing; neonatal infection; neonatal period; neuroinflammation; neuroprotection; offspring; patient population; postnatal; prenatal intervention; prevent; protective effect; protein expression; pup; relating to nervous system; task analysis; transcriptome sequencing; undergraduate student

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.

项目摘要 神经炎症与广泛的疾病相关，包括认知和精神疾病。 健康失调治疗和减少神经炎症仍然是一个医学挑战。的 本研究的目的是确定母体寄生蠕虫对新生儿的影响， 和成年后代，特别关注对小胶质细胞功能和炎症的影响， 寿命以及成年期的露营依赖行为。正如以前的工作所显示的， 新生儿感染通过改变小胶质细胞功能改变神经炎症， 对成年人的学习和记忆有负面影响。目前在患有非- 传染性炎症性疾病，如多发性硬化症，表明用 寄生虫病可能是药物治疗之外的一种新的干预形式。 共栖生物为了生存会发出抗炎信号，这些信号可能 通过减少宿主体内的炎症而具有潜在的益处。以前的工作表明， 母体寄生虫定植可减轻新生儿感染后子代的神经炎症 大肠杆菌感染。同样的工作表明，母亲和断奶的结合， 后代寄生虫定植挽救了依赖于环境恐惧的学习缺陷 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。 蠕虫定植以及定义的持续时间和时间过程的影响， 母体寄生虫定植在我们的新生儿感染模型。这项提案将检验这一假设 母亲寄生虫殖民本身就足以保护后代免受终身影响， 通过减少海马体内的炎症，在整个生命周期中减少新生儿感染。它将 还描述了母体蠕虫定植对后代的影响，以探索可能的 机制，包括分离的细胞群（小胶质细胞，星形胶质细胞和 神经元）从中枢神经系统。重要的是，该项目建议参与和培训 每年约有8名本科生在实验室与啮齿动物一起进行行为任务 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PCR以及NextGen RNA测序的生物信息学项目。这些 研究将阐明母体蠕虫影响的潜在机制， 作为对免疫介导的炎症性疾病易感人群的干预措施。