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

项目摘要/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(NDDS)。尽管在识别基因和环境方面已经取得了进展 NDD-风险因素，我们落后于对环境因素如何作用于某些特定因素的严格调查 改变神经发育的遗传脆弱性。我的论文项目建立在我的联合赞助人布拉泽博士的基础上， 最近的人类流行病学研究表明，婴儿接触头孢菌素是一种环境因素 与新城疫风险增加相关的因素。众所周知，抗生素会降低物种的多样性和 肠道中丰富的有益微生物类群，因此可以改变大脑的结构和功能。 然而，抗生素诱导的扰动微生物群早期影响的机制(S) NDD发病机制中涉及的神经发育过程在很大程度上仍不清楚。我目前的工作 通过研究环境对一种新基因的肠道-微生物-脑的相互作用来解决这一研究空白 在Emanuel DiCicco-Bloom博士(发起人，神经科学)的指导下建立(GxE)NDDS小鼠模型 和马丁·布拉泽(微生物学联合发起人)。目标1的主要目标是接受严格的培训 F99期的微生物学和发育神经生物学研究头孢菌素的早期生命 暴露会改变肠道微生物群，从而导致神经发育失调。建议数 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个基因，它们是研究NDD发病机制的可靠的遗传风险模型 在人/16pDel杂合子中也观察到缺失区。我的初步发现是性行为--还有 头孢菌素暴露对神经发育改变的基因依赖性影响。其余的F99 阶段，我将完成对早期接触头孢菌素如何改变神经发育和肠道的特征- 然后结合一种机械方法来确定微生物组的修复是否可以挽救 改变了神经发育。这次培训将为我提供强大的技术和智力技能，使我能够继续 以博士后身份从事肠道-微生物-脑研究。然而，我在技能上的一个差距是2 将展开的是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-脑GxE相互作用。为了确保我能解决这个问题，我会找一位博士后 实验室，可以训练我常规的和尖端的技术来研究和操纵代谢组和 K00期的表观基因组。这些研究将共同建立和建立一个机械框架 研究肠道-微生物-脑GxE相互作用，同时促进我的道路 作为一名神经科学研究人员的独立性。

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.