Prospective Multi-Omic Analysis of At-Risk infants to Model Celiac Disease Pathogenesis

对高危婴儿进行前瞻性多组学分析以模拟乳糜泻发病机制

• 批准号: 10412934
• 负责人: Maureen Michelle Leonard
• 金额: $ 19.98万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10412934
• 关键词: Affect; Alleles; Antibiotics; Antibodies; Area; Autoimmune Diseases; Autoimmune Process; Autoimmunity; Bioinformatics; Biological; Biological Process; Biopsy; Birth; Celiac Disease; Cells; Child; Chronic; Clinical; Clinical Data; Clinical Investigator; Clinical Medicine; Clinical Trials Design; Cohort Studies; Complex; Computational Biology; Computer Analysis; Computer Models; Data; Data Collection; Development; Diet; Disease; Disease remission; Duodenum; Environmental Risk Factor; Epigenetic Process; Exposure to; Funding; Gene Expression; Generations; Genes; Genetic; Genetic Predisposition to Disease; Genomics; Gluten; Goals; HLA Antigens; Histone Deacetylase; IL6 gene; Immune; Immune response; Immunologic Surveillance; Immunology; Incidence; Individual; Infant; Inflammation; Infrastructure; Ingestion; Interleukin-1; Investigation; K-Series Research Career Programs; Knowledge; Link; Macrophage Activation; Manuscripts; Medical Genetics; Mentored Patient-Oriented Research Career Development Award; Mentors; Mentorship; Metagenomics; Microbe; Modeling; Multiomic Data; Onset of illness; Pathogenesis; Pathway interactions; Patients; Play; Population; Positioning Attribute; Predisposition; Prevalence; Research Personnel; Research Proposals; Risk; Role; Sampling; Susceptibility Gene; System; Training; United States; United States National Institutes of Health; Work; base; career; clinical investigation; cohort; disorder control; disorder prevention; disorder risk; dysbiosis; gene environment interaction; genetic association; genome-wide analysis; gut microbiome; individualized prevention; insight; metagenome; microbiome; microbiome alteration; microbiome analysis; microbiome composition; monocyte; multidisciplinary; multiple omics; nutrition; pathogen; personalized medicine; programs; prospective; single cell sequencing; single-cell RNA sequencing; transcriptome sequencing; transcriptomics; translational medicine; translational study

Project Summary Globally there is a tremendous rise in the incidence of autoimmune disease including celiac disease (CD). CD is unique among autoimmune disorders in that the genetic predisposition, specific human leukocyte antigen (HLA), auto antibodies produced, and trigger, gluten, are known. However, more than 30% of the population carry the predisposing genes and are exposed to gluten, yet only 2-3% of these individuals develop CD even decades after gluten exposure, suggesting a critical role for additional environmental factors. This finding highlights the crucial gap in knowledge of the earliest steps in CD pathogenesis that occur following the exposure to gluten leading to the loss of tolerance and subsequent development of autoimmunity. To understand the complex interactions involved in the development of disease, detailed data collection and multi-omic analysis must begin before the onset of disease, through the development of disease, and into remission. I have access to a unique prospective longitudinal birth cohort to accomplish this. My work has shown that environmental factors alter the gut microbiome composition and function with potential implications for increasing susceptibility to CD in at-risk infants. My preliminary data suggest that gut microbiome alterations at the species level are present prior to the loss of tolerance to gluten and onset of CD. Therefore, I propose to investigate the role of the gut microbiome as a factor that may play a key role in early steps involved in the onset of the disease. I hypothesize that HLA genetics in combination with environmental factors (delivery mode, diet, and antibiotic exposure) can affect the microbiome composition and function ultimately causing epigenetic changes in immune cells leading to the switch from tolerance to immune response to gluten in genetically predisposed individuals. With guidance from my mentoring team, during this 5 year K23 mentored career development award, my objective is gain expertise in microbiome analysis, immunology, and computational analysis to create integrative models that can identify biologic pathways and clinical factors that contribute to loss of tolerance in children genetically at risk of autoimmunity with the goal of personalized prevention of CD. The proposed project has three major aims. Aim 1 I will identify metagenomic alterations before and after the loss of tolerance to gluten and in relation to environmental factors in infants with CD and controls. In aim 2 I will determine alterations in gene expression of circulating monocytes using single cell RNA sequencing before and after the development of CD and compared to controls. Aim 3 will utilize the multi-omic data to build a integrative models to identify biological pathways that contribute to and may predict CD development in at-risk children. This work will lay the scientific framework to launch my career as an NIH-funded independent clinical investigator who can blend expertise in translational investigation, with clinical expertise in CD, immunology, and bioinformatics, to develop computational models and eventually programs for personalized medicine for patients at risk for autoimmune disease.

项目概要 在全球范围内，包括乳糜泻在内的自身免疫性疾病的发病率急剧上升 （光盘）。 CD 在自身免疫性疾病中是独一无二的，因为遗传易感性、特定的人类 白细胞抗原（HLA）、产生的自身抗体以及触发物、麸质是已知的。但超过30% 的人群携带易感基因并接触麸质，但这些人中只有 2-3% 即使在接触麸质数十年后仍会出现CD，这表明额外的环境因素发挥着关键作用 因素。这一发现凸显了对 CD 发病机制最早步骤的认识存在重大差距 接触麸质会导致耐受性丧失并随后产生自身免疫。 了解疾病发展中涉及的复杂相互作用，详细的数据收集和 多组学分析必须在疾病发生之前开始，贯穿疾病的发展，并深入到 缓解。我可以通过独特的前瞻性纵向出生队列来实现这一目标。 我的工作表明，环境因素会改变肠道微生物组的组成和功能 增加高危婴儿对 CD 的易感性的潜在影响。我的初步数据表明肠道 在失去对麸质的耐受性和 CD 发作之前，物种水平的微生物组改变就已经存在。 因此，我建议研究肠道微生物组作为一个可能在早期疾病中发挥关键作用的因素的作用。 疾病发生的步骤。我假设 HLA 遗传学与环境相结合 因素（分娩方式、饮食和抗生素暴露）会影响微生物组的组成和功能 最终引起免疫细胞的表观遗传变化，导致从耐受到免疫的转变 有遗传倾向的个体对麸质的反应。在我的导师团队的指导下，在这 5 年里 今年 K23 指导的职业发展奖，我的目标是获得微生物组分析方面的专业知识， 免疫学和计算分析来创建可以识别生物途径和 导致具有自身免疫遗传风险的儿童丧失耐受性的临床因素，目的是 CD 的个性化预防。拟议项目有三个主要目标。目标 1 我将识别宏基因组 婴儿麸质耐受性丧失前后的变化以及与环境因素的关系 带 CD 和控件。在目标 2 中，我将使用以下方法确定循环单核细胞基因表达的变化 CD 发生前后的单细胞 RNA 测序以及与对照的比较。目标3将 利用多组学数据建立综合模型来识别有助于和 可以预测高危儿童 CD 的发展。这项工作将为我的职业生涯奠定科学框架 作为 NIH 资助的独立临床研究者，他可以将转化研究方面的专业知识与 CD、免疫学和生物信息学方面的临床专业知识，开发计算模型并最终 针对自身免疫性疾病风险患者的个性化医疗计划。