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

基本信息

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
项目类别：
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

项目摘要

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：先天和适应性免疫细胞的活动需要精确协调，以便有效对广泛病原体的免疫反应。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对抗独特的致病性侮辱。机械上，物种之间基因组的结构变化在获取（或损失）中起着重要作用定义免疫细胞功能活性的调节事件。结构变化是指基因组重排，例如易位，插入，扩增和反转。结构变化在物种之间的基因组中，有可能实质性改变基因的位置和调节性。元素，包括分开具有相似功能的基因簇，将基因迁移到不同的基因染色体，并改变基因座的方向。基因组变化的功能后果物种之间的基于每个变化如何影响负责控制基因的调节事件表达。因此，重要的是要定义物种之间的结构变化如何影响调节提高我们从机械和临床前研究中结合发现的能力的原则调节人类免疫反应。在此应用中，我们将定义结构变化小鼠和人类基因组之间会影响控制基因所涉及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在小鼠和人类基因组之间影响1）基因组拓扑，2）调节事件位置拓扑结构域边界，3）基因可用的增强剂景观，4）远程增强子促销相互作用的基因相互作用，在小鼠和人类免疫之间表达差异细胞。我们将测试小鼠与人之间不同调节事件的功能后果免疫细胞，重点是定义有助于LPS诱导的差异的调节事件 NOS2（编码诱导一氧化氮合酶； iNOS）在小鼠和人巨噬细胞中的表达，以及我们将使用它来构建反映人类表达的鼠标模型。鼠标是最广泛的使用人类免疫反应的临床前模型，我们的提案中的研究将有助于了解模型生物基因组与人基因组之间的结构变化如何有助于获取不同细胞类型和刺激依赖性基因表达模式的物种和功能。它还可以预测小鼠中定义的机制如何转化为人类以及构建小鼠模型，可以更好地反映临床前研究的人类免疫反应。