Non-genetic inheritance: mechanisms of microbiome-mediated transgenerational change

项目摘要 与动物相关的密集微生物群落，称为微生物组，可以具有 对寄主发育和生理都有重要影响。然而，我们才刚刚开始 了解微生物群促进这些重要功能的机制。的确有 非常有兴趣定义和了解这些关联，例如组成的变化，或 生物失调，与许多疾病有关。此外，操纵或恢复 微生物组正被作为治疗的靶点。而粪便移植治疗的成功 急性和慢性艰难梭菌感染突出了它们的潜力，更广泛的适用性 对其他疾病的这种治疗方法仍不清楚。因此，我们非常需要了解 寄主与其微生物群的关系及其调控和分子机制 信令机制。我打算利用果蝇，黑腹果蝇，来研究 有助于建立正常寄主生理条件的机制，一个关键的 制定微生物组治疗策略的步骤。我的项目将重点放在时间和 寄主生理发育正常参数的建立。具体地说，我将在 无菌果蝇和经历过破坏微生物组的早期生活事件的果蝇，后者 在其他动物模型中，它与慢性疾病有关。这一行动的具体目标 建议是：a)探索微生物区系对D。 黑猩猩。B)确定促进正常寄主生理的寄主和微生物区系因素。c) 制定策略，通过操纵 微生物组。我将使用转录本形式的高通量测序技术， 代谢物和表观基因组研究苍蝇的基因表达和代谢物产生 发育和代代相传，加上传统的遗传方法来表征 确定了目标。我的实验将重点放在与无菌、灵知菌和 传统饲养的苍蝇，以表征宿主与微生物群结合的影响。这就做 还要识别引起宿主变化的微生物信号，并在实验中操纵这两种信号 调节这些联系的宿主和微生物识别和信号系统。给定 高度保守的文件和人类之间的发育和动态平衡信号通路， 75%的已知人类疾病基因在黑腹果蝇基因组中有匹配，即 预计这项工作将确定调节宿主微生物组的保守机制 包括人类在内的所有动物之间的相互作用。

Project Summary The dense microbial communities associated with animals, referred to as the microbiome, can have an important impact on both host development and physiology. Yet, we are only beginning to understand the mechanisms by which the microbiome promotes these important functions. There is great interest to define and understand how these associations, such as changes in composition, or dysbiosis, are linked to a number of diseases. Moreover, the ability to manipulate or restore the microbiome is being pursued as a therapeutic target. While the success of fecal transplant therapy for acute and chronic Clostridium difficile infections highlights their potential, the broader applicability of such therapies to other maladies remains unknown. Consequently, there is great need to understand the relationship between a host and its microbiome with regards to its regulation and molecular signaling mechanisms. I propose to utilize the fruit fly, Drosophila melanogaster, to investigate mechanisms that contribute to the establishment of normal host physiological conditions, a critical step in developing strategies for microbiome therapy. My project will focus on the timing and establishment of normal parameters of host physiology and development. Specifically, I will study in germ-free flies and flies that have experienced early-life events that disrupt the microbiome, the latter of which has been linked to chronic diseases in other animal models. The specific goals of this proposal are to: a) Explore the trans-generational impacts of the microbiota on D. melanogaster. b) Identify host and microbiota factors that promote normal host physiology. c) Develop strategies to restore normal animal physiology through manipulation of the microbiome. I will use high throughput sequencing technologies in the form of transcriptomes, metabolomes, and epigenomes to investigate gene expression and metabolite production across fly development and through generations, coupled with traditional genetic approaches to characterize identified targets. My experiments will focus on comparisons with germ-free, gnotobiotic, and conventionally-reared flies to characterize the effects of host association with the microbiome. I will also identify microbial signals that induce changes in the host and will experimentally manipulate both the host and microbial recognition and signaling systems that mediate these associations. Given the high conservation of developmental and homeostatic signaling pathways between files and humans, and that 75% of known human disease genes have a match in the D. melanogaster genome, I anticipate that this work will identify conserved mechanisms that regulate host-microbiome interactions in all animals, including humans.