Impact of microbial exposure on immune development

微生物暴露对免疫发育的影响

• 批准号: 9789838
• 负责人: Brian David Rudd
• 金额: $ 46.53万
• 依托单位: CORNELL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-24 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9789838
• 关键词: ATAC-seq; Adaptive Immune System; Adult; Affect; Age; Animals; Asthma; Birth; CD8-Positive T-Lymphocytes; CD8B1 gene; Cell Compartmentation; Cells; Cellular Immunity; Cytotoxic T-Lymphocytes; Data; Development; Disease; Elderly; Environment; Event; Exhibits; Exposure to; Failure; Genomic approach; Goals; Growth; Hypersensitivity; Immune; Immune response; Immune system; Immunity; Individual; Infection; Infection Control; Inflammatory; Inflammatory Bowel Diseases; Insulin-Dependent Diabetes Mellitus; Knowledge; Label; Life; Link; Listeria monocytogenes; Mediating; Microbe; Molecular; Mothers; Mus; Neonatal; Peripheral; Phenotype; Play; Positioning Attribute; Predisposition; Pregnancy; Production; Resistance; Role; Shapes; Signal Transduction; T cell response; T-Cell Development; T-Lymphocyte; Testing; arm; cell behavior; disorder risk; fetal; fetal loss; germ free condition; improved; in utero; innovation; insight; interest; microbial; microbial colonization; microbiota; migration; mouse model; novel; offspring; pathogen; programs; response; tool; transcriptome sequencing

Project Summary / Abstract The exposure to microbes in utero and after birth permanently programs an individual’s immune system and life- long disease risk. However, the relationship between microbial exposure and immune ontogeny remain poorly defined. We have developed a mouse model to better understand how the maternal microbial environment shapes the offspring’s immune system. Our preliminary data indicates that the timing of microbial exposure has a profound impact on susceptibility to intracellular pathogens later in life. Thus, a main objective of this proposal is to dissect out how maternal microbial exposure alters the development and function of the offspring’s CD8+ T cells. To accomplish this objective, we will use a number of cutting-edge approaches to test the hypothesis that microbial exposure programs immune susceptibility by altering the developmental layers of the CD8+ T cell response to infection. In the first, aim we will determine how microbial exposure changes the way the CD8+ T cell compartment is ‘put-together.’ Results from this aim will provide insight into how the composition and programming of CD8+ T cells in the offspring are linked to microbial exposure in the earliest days of life. In the second aim, we will examine how the amount and timing of microbial exposure alter the offspring’s response to intracellular pathogens. We are particularly interested in determining how microbial exposure during specific windows of development (in utero, post-natal) changes the offspring’s CD8+ T cell response to infection later in life. Our proposal aims to provide a new conceptual framework for understanding how microbial colonization in early life leads to life-long, potentially irreversible, changes in the offspring’s immune system. Knowledge gained from these studies is expected to broaden our fundamental understanding of immune development and cell- mediated immunity.

项目总结/摘要 在子宫内和出生后接触微生物会永久性地编程个体的免疫系统和生命- 长期患病风险然而，微生物暴露和免疫个体发育之间的关系仍然很差 定义了我们已经开发了一种小鼠模型，以更好地了解母体微生物环境如何 塑造后代的免疫系统我们的初步数据表明，微生物暴露的时间 对以后生活中细胞内病原体的易感性产生深远影响。因此，本提案的一个主要目标是， 是剖析母体微生物暴露如何改变后代CD 8 + T细胞的发育和功能， 细胞为了实现这一目标，我们将使用一些尖端的方法来测试假设， 微生物暴露通过改变CD 8 + T细胞的发育层来编程免疫易感性 对感染的反应。首先，我们将确定微生物暴露如何改变CD 8 + T细胞的表达方式。 细胞隔室是“组装在一起”。从这个目标的结果将提供洞察如何组成和 后代中CD 8 + T细胞的编程与生命早期的微生物暴露有关。在 第二个目标，我们将研究微生物暴露的数量和时间如何改变后代对 胞内病原体我们特别感兴趣的是确定微生物暴露在特定的 发育窗口（子宫内，出生后）改变了后代的CD 8 + T细胞对感染的反应， 生活我们的建议旨在提供一个新的概念框架，以了解微生物如何在 早期生命导致后代免疫系统终身的、可能不可逆转的变化。获得的知识 这些研究有望拓宽我们对免疫发育和细胞的基本理解， 介导免疫。