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.

项目概要 神经炎症与多种疾病相关，包括认知和精神疾病 健康障碍。治疗和减少神经炎症仍然是一个医学挑战。这 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 寿命以及成年期海马依赖性行为。正如之前的工作所示， 新生儿感染通过改变小胶质细胞功能来改变神经炎症，并且具有持久的、 对成人的学习和记忆产生负面影响。当前针对患有非疾病的患者群体的工作 传染性炎症性疾病，例如多发性硬化症，表明治疗 共生寄生虫可能是药物治疗之外的一种新的干预形式。 共生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具有​​潜在的好处。之前的工作表明 新生儿体内寄生虫定植可减轻后代的神经炎症 大肠杆菌感染。同一项工作表明，母婴和断奶的结合 后代蠕虫定植可挽救海马依赖性情境恐惧的学习缺陷 调节任务。需要进一步的研究来了解母体对后代的影响 单独的蠕虫定植以及确定其影响的持续时间和时间进程 我们的新生儿感染模型中母体蠕虫定植。该提案将检验假设 仅母体蠕虫定植就足以保护后代免受寄生虫的终生影响 通过在整个生命周期中减少海马体内的炎症来预防新生儿感染。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，包括分离细胞群（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 名本科生在实验室与啮齿类动物一起完成行为任务 分析以及细胞和分子分析技术，例如免疫组织化学和 实时定量 PCR 以及使用 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，可以进一步研究 探索对易受免疫介导的炎症性疾病影响的人群进行干预。