Impact of early microbial exposure on immune ontogeny

项目总结/摘要： 生命早期的微生物暴露可以永久地编程后代的免疫系统和终身疾病的风险。 例如，暴露在农场环境中的儿童患哮喘的可能性较小， 寿命与患炎症性肠病和糖尿病的风险增加有关。最近的研究 我也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，这些研究都是基于流行病学的关联，以及潜在的机制， 仍然未定义。在这个行政补充，我们将利用一个独特的宠物店'脏'鼠标模型， 确定微生物环境如何改变造血干细胞产生免疫细胞 （HSC）。我们的初步数据表明，在肮脏环境中长大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HSC产生的“快速作用”淋巴细胞和更少的“缓慢作用”淋巴细胞 由成年HSC制造。然而，迄今为止，我们所有的研究都是用成熟的淋巴细胞进行的， 我们还需要探索微生物环境对HSC隔室的影响。因此，我们寻求 基金使用单细胞RNA-seq平台来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提供关键的见解， 微生物环境导致免疫发育和晚年对 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.