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:
- 金额:$ 54.97万
- 依托单位:
- 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:
- 关键词:3-DimensionalAffectAttentionBiomedical ResearchBuffersCategoriesCell Differentiation processCell physiologyCellsChromosomal RearrangementChromosomesClinical TrialsCommunicable DiseasesConserved SequenceDNA SequenceData SetElementsEnhancersEventFoundationsGene ClusterGene ExpressionGene Expression ProfileGene Expression RegulationGenesGeneticGenetic Enhancer ElementGenomeGenomic approachGenomicsGrantHumanHuman GenomeImmuneImmune responseImmunityImmunological ModelsImmunologicsImmunologyKnowledgeLocationMacrophageMusNOS2A geneNitric Oxide SynthasePathogenicityPathologyPatientsPlayPositioning AttributePre-Clinical ModelPrimatesRegulationRegulatory ElementResearchRodentRoleSiteTechnologyTestingTherapeuticTranslatingTranslocation BreakpointTreesVaccine DesignVariantcell typecombatdifferential expressiongene interactionhuman modelimprovedinducible gene expressioninhibitorinsertion/deletion mutationinsightmodel organismmouse genomemouse modelnovelpathogenpreclinical studypreferencepressurepreventpromoterresponsetool
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: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。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Amy Susan Weinmann其他文献
Amy Susan Weinmann的其他文献
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{{ truncateString('Amy Susan Weinmann', 18)}}的其他基金
The Molecular Mechanisms of Immune Cell Development and Function
免疫细胞发育和功能的分子机制
- 批准号:
10751580 - 财政年份:2023
- 资助金额:
$ 54.97万 - 项目类别:
Molecular characterization of the role for metabolites in immune cell differentiation
代谢物在免疫细胞分化中作用的分子表征
- 批准号:
10455211 - 财政年份:2021
- 资助金额:
$ 54.97万 - 项目类别:
Tet1 activity and function in helper T cells
辅助 T 细胞中的 Tet1 活性和功能
- 批准号:
8897261 - 财政年份:2014
- 资助金额:
$ 54.97万 - 项目类别:
Tet1 activity and function in helper T cells
辅助 T 细胞中的 Tet1 活性和功能
- 批准号:
8754547 - 财政年份:2014
- 资助金额:
$ 54.97万 - 项目类别:
Molecular Characterization of T-bet's Role in Immunity
T-bet 在免疫中的作用的分子表征
- 批准号:
6811196 - 财政年份:2004
- 资助金额:
$ 54.97万 - 项目类别:
Molecular Characterization of T-bet's Role in Immunity
T-bet 在免疫中的作用的分子表征
- 批准号:
8414841 - 财政年份:2004
- 资助金额:
$ 54.97万 - 项目类别:
Molecular Characterization of T-bet's Role in Immunity
T-bet 在免疫中的作用的分子表征
- 批准号:
8212463 - 财政年份:2004
- 资助金额:
$ 54.97万 - 项目类别:
Molecular characterization of the role for T-bet and Bcl-6 in immune cell metabolism and differentiation
T-bet 和 Bcl-6 在免疫细胞代谢和分化中作用的分子表征
- 批准号:
9241941 - 财政年份:2004
- 资助金额:
$ 54.97万 - 项目类别:
Molecular Characterization of T-bet's Role in Immunity
T-bet 在免疫中的作用的分子表征
- 批准号:
6892078 - 财政年份:2004
- 资助金额:
$ 54.97万 - 项目类别:
Molecular Characterization of T-bet's Role in Immunity
T-bet 在免疫中的作用的分子表征
- 批准号:
7230470 - 财政年份:2004
- 资助金额:
$ 54.97万 - 项目类别:
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