Impact of early microbial exposure on immune ontogeny

项目摘要/摘要： 生命早期接触微生物可能会永久性地对后代的免疫系统和终身疾病风险进行编程。 例如，暴露在农场环境中的儿童患哮喘的可能性较小，早期使用抗生素的可能性较小 生活与患炎症性肠病和糖尿病的风险增加有关。最新研究 还观察到剖腹产与糖尿病、哮喘和过敏性疾病之间的相关性 在以后的生活中。然而，这些研究是基于流行病学的相关性和潜在的机制 仍然没有定义。在这份行政补充中，我们将利用宠物店的一种独特的“脏”老鼠模型来 确定微生物环境如何改变从造血干细胞产生免疫细胞 (HSCs)。我们的初步数据表明，在肮脏环境中饲养的成年老鼠对感染的抵抗力更强。 因为它们含有更多由胎儿HSCs产生的“快作用”淋巴细胞和较少的“慢作用”淋巴细胞 由成年的造血干细胞制成。然而，到目前为止，我们所有的研究都是用成熟的淋巴细胞进行的，并且 我们还没有探索微生物环境对HSC隔间的影响。因此，我们正在寻求 使用单细胞rna-seq平台研究微生物环境如何改变从 胎儿到成人的造血。从这些研究中获得的知识将为我们提供关于早期 微生物环境导致免疫发育和晚年易感性的永久性变化 疾病。

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.