Examination of gut-microbiome-brain interactions in a novel gene x environment model of neurodevelopmental disorders

项目概要/摘要 神经系统的发育是一个复杂的、动态的过程， 神经发育障碍（NDD）。尽管在确定遗传和环境因素方面取得了进展， NDD风险因素，我们落后于严格的调查，环境因素如何可能对某些 基因缺陷来改变神经发育我的论文项目是建立在我的共同赞助人，布拉泽博士的基础上的， 最近的人类流行病学研究确定婴儿头孢菌素类抗生素暴露是一种环境因素， 与NDD风险增加相关的因素。众所周知，抗生素降低了生物多样性， 肠道中丰富的有益微生物类群，从而改变大脑结构和功能。 然而，抗生素诱导的扰动微生物组影响早期 NDD发病机制中涉及的神经发育过程仍然在很大程度上未被探索。我目前的工作 通过研究环境中新基因的肠道-微生物组-大脑相互作用来解决这一研究空白 (GxE)在Emanuel DiCicco-Bloom博士（申办方，神经科学）的监督下，建立NDD小鼠模型 和Martin Blaser（共同发起人，微生物学）。目标1的主要目标是接受严格的训练， 微生物学和发育神经生物学在F99阶段，以研究如何早期生命头孢菌素 暴露改变了肠道微生物组，并因此使神经发育失调。拟议 实验将利用野生型和16p11.2微缺失拷贝数变异（+/16 pDel CNV）小鼠， 这是一个强大的遗传风险模型，研究NDD发病机制，由于其高度保守的28个基因 在人+/16 pDel杂合子中也观察到缺失区。我的初步调查结果显示性行为 头孢菌素暴露对神经发育改变的基因型依赖性影响。关于F99 阶段，我将完成表征如何早期生活头孢菌素暴露改变神经发育和肠道- 微生物组，然后采用机械方法来确定微生物组恢复是否可以挽救 改变神经发育。这项培训将为我提供一个强大的技术和智力技能，以继续 作为博士后研究肠道-微生物组-大脑的研究。然而，在我的技能差距，目标2 将扩大是分析和解释代谢组和表观基因组，两个中间系统的能力 介导肠道-微生物组-大脑GxE相互作用。为了确保我解决这个差距，我将确定一个博士后 实验室，可以训练我在常规和尖端技术研究和操纵代谢组学， K 00阶段的表观基因组。这些研究将共同建立和建立一个机制框架 研究肠道-微生物组-大脑GxE相互作用，同时促进我的道路， 作为神经科学研究者的独立性

PROJECT SUMMARY / ABSTRACT The development of the nervous system is a complex, dynamic process that is dysregulated in neurodevelopmental disorders (NDDs). Although progress has been made to identify genetic and environmental NDD-risk factors, we lag behind with rigorous investigation of how environmental factors may act on certain genetic vulnerabilities to alter neurodevelopment. My dissertation project builds on my co-sponsor, Dr. Blaser’s, recent human epidemiological study that identified infant cephalosporin antibiotic exposure as an environmental factor associated with increased NDD risk. It is well established that antibiotics decrease the diversity and abundance of beneficial microbial taxa in the gut, which can consequently alter brain structure and function. However, the mechanism(s) by which an antibiotic-induced perturbed microbiome affects early neurodevelopmental processes implicated in NDD pathogenesis remains largely unexplored. My current work addresses this research gap by investigating gut-microbiome-brain interactions in a novel gene by environment (GxE) mouse model of NDDs under the supervision of Drs. Emanuel DiCicco-Bloom (sponsor, neuroscience) and Martin Blaser (co-sponsor, microbiology). The primary goal of Aim 1 is to receive rigorous training in microbiology and developmental neurobiology during the F99 phase to examine how early life cephalosporin exposure alters the gut microbiome and consequentially dysregulates neurodevelopment. The proposed experiments will utilize both wildtype and 16p11.2 microdeletion copy number variation (+/16pDel CNV) mice, which are a robust genetic risk model for investigating NDD pathogenesis due to their highly conserved 28 gene deletion region also observed in human +/16pDel heterozygotes. My preliminary findings indicate sex- and genotype-dependent effects of cephalosporin exposure on altered neurodevelopment. For the remaining F99 phase, I will finish characterizing how early life cephalosporin exposure alters neurodevelopment and the gut- microbiome and then incorporate a mechanistic approach to determine if microbiome restoration can rescue altered neurodevelopment. This training will provide me with a strong technical and intellectual skillset to continue investigating gut-microbiome-brain research as a postdoctoral scholar. However, a gap in my skillset that Aim 2 will expand on is the ability to analyze and interpret the metabolome and epigenome, two intermediate systems that mediate gut-microbiome-brain GxE interactions. To ensure I address this gap, I will identify a postdoctoral laboratory that can train me in routine and cutting-edge techniques to study and manipulate the metabolome and epigenome during the K00 phase. These studies will collectively establish and build on a mechanistic framework to investigate gut-microbiome-brain GxE interactions while simultaneously facilitating my path towards independence as a neuroscience investigator.