Impact of early microbial exposure on immune ontogeny

早期微生物暴露对免疫个体发育的影响

• 批准号: 10747605
• 负责人: Miles Philip Davenport
• 金额: $ 33.52万
• 依托单位: CORNELL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-24 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10747605
• 关键词: Administrative Supplement; Adult; Allergic; Antibiotics; Asthma; Birth; Cell Compartmentation; Cesarean section; Child; Data; Development; Diabetes Mellitus; Disease; Elderly; Environment; Epidemiology; Exposure to; Farming environment; Funding; Generations; Goals; Growth; Hematopoiesis; Hematopoietic stem cells; Immune; Immune System Diseases; Immune system; Infection; Inflammatory Bowel Diseases; Knowledge; Life; Lymphocyte; Maternal-Fetal Exchange; Mature Lymphocyte; Mus; Predisposition; Preventive; Resistance; Risk; Therapeutic; disorder risk; fetal; insight; microbial; mouse model; novel; offspring; programs; single-cell RNA sequencing; stem cells

PROJECT SUMMARY / ABSTRACT: Early life microbial exposure can permanently program the offspring’s immune system and life-long disease risk. For example, children exposed to farm environments are less likely to develop asthma, and antibiotic use in early life is associated with an increased risk of developing inflammatory bowel disease and diabetes. Recent studies have also observed a correlation between cesarean section birth and diabetes, asthma and allergic disorders later in life. However, these studies are based on epidemiological associations, and the underlying mechanisms remain undefined. In this administrative supplement, we will leverage a unique pet-shop ‘dirty’ mouse model to determine how the microbial environment alters the generation of immune cells from hematopoietic stem cells (HSCs). Our preliminary data indicates that adult mice raised in a dirty environment are more resistant to infection because they contain more ‘fast-acting’ lymphocytes made by fetal HSCs and fewer ‘slower-acting’ lymphocytes made by adult HSCs. However, all of our studies to date have been performed with mature lymphocytes, and we have yet to explore the impact of the microbial environment on the HSC compartment. Thus, we are seeking funds to use a single-cell RNA-seq platform to examine how the microbial environment alters the transition from fetal to adult hematopoiesis. Knowledge gained from these studies will provide key insights into how the early microbial environment leads to permanent changes in immune development and later-life susceptibility to disease.

项目摘要 /摘要： 早期生命微生物暴露可以永久编程后代的免疫系统和终身疾病风险。 例如，暴露于农场环境的儿童不太可能患哮喘，早期使用抗生素 生命与患炎症性肠病和糖尿病的风险增加有关。最近的研究 还观察到剖宫产分娩与糖尿病，哮喘和过敏性疾病之间的相关性 后来生活。但是，这些研究基于流行病学关联和潜在的机制 保持不确定。在这种管理补充剂中，我们将利用独特的宠物店“ Dirty”鼠标模型 确定微生物环境如何改变造血干细胞的免疫细胞的产生 （HSC）。我们的初步数据表明，在肮脏的环境中饲养的成年小鼠对感染更具抵抗力 因为它们包含胎儿HSC制造的更多“快速作用”淋巴细胞，较少的“慢性”淋巴细胞 由成人HSC制成。但是，迄今为止我们的所有研究都是用成熟的淋巴细胞进行的，并且 我们尚未探索微生物环境对HSC隔室的影响。那我们正在寻找 使用单细胞RNA-seq平台的资金来检查微生物环境如何改变从 胎儿到成人造血。从这些研究中获得的知识将为早期如何提供关键的见解 微生物环境会导致免疫发育的永久变化和后来的生活敏感性 疾病。