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，在 神经发育障碍（NDD）。尽管在识别遗传和环境方面已经取得了进展 NDD-风险因素，我们在严格调查环境因素如何作用于某些方面方面落后了 改变神经发育的遗传脆弱性。我的论文项目建立在我的共同资助者 Blaser 博士的基础上， 最近的人类流行病学研究确定婴儿头孢菌素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，抗生素会降低多样性并 肠道中含有丰富的有益微生物类群，从而可以改变大脑结构和功能。 然而，抗生素引起的微生物组紊乱影响早期的机制 NDD 发病机制中涉及的神经发育过程在很大程度上仍未被探索。我目前的工作 通过研究环境下新基因中的肠道-微生物组-大脑相互作用来解决这一研究空白 (GxE) 博士监督下的 NDD 小鼠模型。 Emanuel DiCicco-Bloom（神经科学赞助商） 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培训 F99 阶段的微生物学和发育神经生物学，以研究早期头孢菌素如何 暴露会改变肠道微生物群，从而导致神经发育失调。拟议的 实验将利用野生型和 16p11.2 微缺失拷贝数变异 (/16pDel CNV) 小鼠， 由于其高度保守的 28 基因，它们是研究 NDD 发病机制的强大遗传风险模型 在人类 /16pDel 杂合子中也观察到缺失区域。我的初步发现表明性别和 头孢菌素暴露对神经发育改变的基因型依赖性影响。对于剩下的F99 阶段，我将完成对生命早期接触头孢菌素如何改变神经发育和肠道的描述。 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。这次培训将为我提供强大的技术和智力技能，以便我继续 作为博士后学者研究肠道微生物组大脑研究。然而，我的技能上的差距导致《Aim 2》 将扩展分析和解释代谢组和表观基因组这两个中间系统的能力 介导肠道-微生物组-大脑 GxE 相互作用。为了确保解决这一差距，我将确定一名博士后 实验室可以训练我研究和操纵代谢组的常规和尖端技术 K00 阶段的表观基因组。这些研究将共同建立并建立一个机械框架 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.