Genome organization, evolutionary structural variation, and gene regulation in immunity

免疫中的基因组组织、进化结构变异和基因调控

• 批准号: 10662147
• 负责人: Amy Susan Weinmann
• 金额: $ 54.97万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-26 至 2027-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10662147
• 关键词: 3-Dimensional; Affect; Attention; Biomedical Research; Buffers; Categories; Cell Differentiation process; Cell physiology; Cells; Chromosomal Rearrangement; Chromosomes; Clinical Trials; Communicable Diseases; Conserved Sequence; DNA Sequence; Data Set; Elements; Enhancers; Event; Foundations; Gene Cluster; Gene Expression; Gene Expression Profile; Gene Expression Regulation; Genes; Genetic; Genetic Enhancer Element; Genome; Genomic approach; Genomics; Grant; Human; Human Genome; Immune; Immune response; Immunity; Immunological Models; Immunologics; Immunology; Knowledge; Location; Macrophage; Mus; NOS2A gene; Nitric Oxide Synthase; Pathogenicity; Pathology; Patients; Play; Positioning Attribute; Pre-Clinical Model; Primates; Regulation; Regulatory Element; Research; Rodent; Role; Site; Technology; Testing; Therapeutic; Translating; Translocation Breakpoint; Trees; Vaccine Design; Variant; cell type; combat; differential expression; gene interaction; human model; improved; inducible gene expression; inhibitor; insertion/deletion mutation; insight; model organism; mouse genome; mouse model; novel; pathogen; preclinical study; preference; pressure; prevent; promoter; response; tool

Abstract: The activities of innate and adaptive immune cells need to be precisely coordinated for an effective immune response to a wide-range of pathogens. There are many similarities between immune responses in different species, but each species also has adapted to combat unique pathogenic insults. Mechanistically, structural variation in the genome between species plays a prominent role in the acquisition (or loss) of regulatory events involved in defining the functional activity of immune cells. Structural variation refers to genome rearrangements such as translocations, insertions, amplifications, and inversions. Structural variation in the genome between species has the potential to substantially alter the placement of genes and regulatory elements, including splitting apart clusters of genes with similar functions, relocating genes to different chromosomes, and changing the orientation of loci. The functional consequences for changes in the genome between species are based on how each change affects the regulatory events responsible for controlling gene expression. Therefore, it is important to define how structural variation between species affects regulatory principles to improve our ability to relate findings from mechanistic and preclinical studies in model organisms to the regulation of the human immune response. In this application, we will define how structural variation between the mouse and human genomes influences the regulatory events involved in controlling genes that are differentially expressed in mouse and human immune cells. We will determine how structural variation between the mouse and human genomes affects the 1) topology of the genome, 2) regulatory events that position topological domain boundaries, 3) enhancer landscape available to genes, and 4) long-range enhancer-promoter interactions for genes with differences in expression between mouse and human immune cells. We will test the functional consequences for divergent regulatory events between mouse and human immune cells, with a focus on defining the regulatory events contributing to differences in the LPS-inducible expression of Nos2 (encodes inducible nitric oxide synthase; iNOS) in mouse and human macrophages, and we will use this to build a mouse model reflecting human expression. The mouse is one of the most widely used preclinical models of the human immune response, and the studies in our proposal will aid in understanding how structural variation between the genomes of model organisms and the human genome contribute to species acquiring different cell-type and stimulation-dependent gene expression patterns and functions. It will also make it possible to predict how mechanisms defined in mice translate to human as well as build mouse models that better reflect human immune responses for pre-clinical studies.

摘要：天然免疫细胞和获得性免疫细胞的活动需要精确协调才能有效 对多种病原体的免疫反应。在免疫反应之间有许多相似之处 不同的物种，但每个物种也适应了独特的病原体侮辱。从机械上讲， 物种间基因组的结构差异在获得(或丢失) 参与定义免疫细胞功能活动的调节事件。结构变异指的是 基因组重排，如易位、插入、扩增和倒置。结构变化 在物种之间的基因组中有可能极大地改变基因的位置和调控 元素，包括分裂具有相似功能的基因簇，将基因重新定位到不同的 染色体，以及改变基因座的方向。基因组变化的功能后果 物种之间的差异是基于每个变化如何影响负责控制基因的调控事件 表情。因此，确定物种之间的结构差异如何影响调控是很重要的。 提高我们在模式生物中联系机械学和临床前研究结果能力的原则 对人类免疫反应的调节。在本应用程序中，我们将定义结构变化如何 小鼠和人类基因组之间的关系会影响涉及控制基因的调节事件 在小鼠和人类免疫细胞中差异表达。我们将确定结构变化如何 老鼠和人类基因组之间的关系影响1)基因组的拓扑结构，2)调节事件， 定位拓扑域边界，3)基因可用的增强子景观，以及4)远程 小鼠和人免疫差异表达基因的增强子-启动子相互作用 细胞。我们将测试小鼠和人类之间不同调控事件的功能后果 免疫细胞，重点是定义导致内毒素诱导的差异的调节事件 NOS2(编码诱导型一氧化氮合酶；iNOS)在小鼠和人巨噬细胞中的表达，以及 我们将利用这一点来建立一个反映人类表情的老鼠模型。鼠标是应用最广泛的 使用人类免疫反应的临床前模型，我们提案中的研究将有助于 理解模式生物基因组和人类基因组之间的结构差异 有助于物种获得不同的细胞类型和刺激依赖的基因表达模式 功能。它还将使人们有可能预测在老鼠身上定义的机制如何翻译给人类以及 为临床前研究建立更能反映人类免疫反应的小鼠模型。