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

在神经发育障碍的新型基因 x 环境模型中检查肠道-微生物组-大脑相互作用

• 批准号: 10610587
• 负责人: Courtney R. McDermott
• 金额: $ 4.14万
• 依托单位: RUTGERS BIOMEDICAL AND HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-15 至 2024-09-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10610587
• 关键词: 16S ribosomal RNA sequencing; 16p11.2; Acute; Address; Affect; Antibiotics; Area; Attention deficit hyperactivity disorder; Autopsy; Bioinformatics; Biological; Brain; Brain region; CCNE1 gene; Cecum; Cells; Cephalosporins; Child; Competence; Complex; Consequentialism; Copy Number Polymorphism; Data; Development; Diagnosis; E protein; Ensure; Environment; Environmental Risk Factor; Epigenetic Process; Etiology; Foundations; Gene Deletion; Gene Expression; Genes; Genetic; Genetic Predisposition to Disease; Genetic Risk; Genotype; Goals; Heterozygote; Hippocampus (Brain); Human; Infant; Intellectual functioning disability; Investigation; Label; Laboratories; Life; Link; Mediating; Microbiology; Modeling; Mus; Neurodevelopmental Disorder; Neurons; Neurosciences; Outcome; Pathogenesis; Phase; Phenotype; Population; Positioning Attribute; Process; Proliferating; Proteins; Research; Research Personnel; Research Project Grants; Risk; Risk Factors; S phase; Saline; Structure; Students; Supervision; System; Techniques; Testing; Training; United States; Work; autism spectrum disorder; brain cell; brain research; calbindin; career; clinical heterogeneity; cohort; dentate gyrus; developmental neurobiology; disorder risk; environmental stressor; epidemiology study; epigenome; experimental study; gene environment interaction; genetic variant; gut bacteria; gut microbiome; human disease; innovation; male; metabolome; metabolomics; microbial; microbiome; microbiota transplantation; microdeletion; mouse model; nerve stem cell; nervous system development; neurodevelopment; neurogenesis; neuroimaging; novel; obesity-associated asthma; post-doctoral training; postnatal; pre-doctoral; reconstitution; restoration; sex; stem cell population; transcriptome sequencing; transcriptomics

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.

项目摘要 /摘要 神经系统的发展是一个复杂的动态过程，在 神经发育障碍（NDDS）。尽管已经取得了进步来识别遗传和环境 NDD风险因素，我们以严格的投资落后于环境因素如何在某些方面起作用 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赞助商Blaser博士的基础上 最近的人类流行病学研究发现婴儿头孢菌素抗生素暴露为环境 与NDD风险增加有关的因素。众所周知，抗生素降低了多样性和 肠道中有益微生物分类群的抽象，因此可以改变大脑的结构和功能。 但是，抗生素诱导的扰动微生物组的机制早期影响 NDD发病机理中实施的神经发育过程在很大程度上仍然是意外的。我目前的工作 通过研究环境中新型基因中的肠道微生物组相互作用来解决这一研究差距 （GXE）在DRS的监督下NDD的小鼠模型。 Emanuel Dicicco-bloom（赞助商，神经科学） 和马丁·布拉瑟（Martin Blaser）（微生物学共同发起人）。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检查早期生命状态孢菌素如何 暴露会改变肠道微生物组，从而改变神经发育。提议 实验将同时使用野生型和16p11.2微骨骼拷贝数变化（+/16pdel CNV）小鼠， 这是一个强大的遗传风险模型，用于研究NDD发病机理，因为它们高度构成28个基因 在人 +/16pdel杂合子中也观察到缺失区域。我的初步发现表明性别 - 头孢菌素暴露对改变神经发育的基因型依赖性作用。剩下的F99 阶段，我将完成表征早期头孢菌素暴露如何改变神经发育和肠道的表征 微生物组，然后结合一种机械方法来确定微生物组是否可以挽救 神经发育改变。这项培训将为我提供强大的技术和智力技能，以继续 将肠道微生物组研究研究为博士后科学。但是，我的技能差距2 将扩展的是分析和解释代谢组和表观基因组的能力，这是两个中间系统 介导肠道 - 微生物组 - 脑gxe相互作用。为了确保我解决这个差距，我将确定博士后 可以培训我的常规和尖端技术的实验室，以研究和操纵代谢组和 在K00期间的表观基因组。这些研究将集体建立和建立在机械框架上 研究肠道 - 微生物脑 - 脑gxe相互作用，同时支持我的道路 独立作为神经科学研究者。