Regulatory mechanisms governing Th17 cell effector identity and plasticity
Regulatory mechanisms governing Th17 cell effector identity and plasticity
批准号:
10376865
负责人:
Maria Ciofani
金额:
$37.36万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
2016
资助国家:
美国
项目状态:
未结题
起止时间:
2016-04-01 至 2025-03-31
关键词:
3-DimensionalAdoptedAdoptionAnti-Inflammatory AgentsArchitectureAutoimmune DiseasesAutoimmunityAutomobile DrivingBacteriaBiological AssayCD4 Positive T LymphocytesCRISPR/Cas technologyCell LineageCell physiologyCellsCharacteristicsChromatinChromatin LoopDiseaseEffector CellElementsEnvironmentExhibitsExperimental Autoimmune EncephalomyelitisFundingGene Expression RegulationGene TargetingGeneticGenetic TranscriptionGenomeGenomicsHelper-Inducer T-LymphocyteImmune responseImmunityInfectionInflammatoryInflammatory Bowel DiseasesInflammatory ResponseInterleukin-17IntestinesKnowledgeMapsMediator of activation proteinMolecularMolecular ConformationMucosal ImmunityMucous MembraneMultiple SclerosisPathogenicityPathologyPlayProteinsPsoriatic ArthritisRegulationRegulator GenesRegulatory ElementRegulatory T-LymphocyteReporterReportingRheumatoid ArthritisRoleSeriesSiteSpinal CordStructureSurfaceT cell differentiationT-LymphocyteT-Lymphocyte SubsetsTherapeutic InterventionWorkautoimmune inflammationcell typecytokineeffector T cellepigenomicsflexibilityfungusin vivomouse modelnovelpreservationprogramstooltraittranscription factor
中文摘要
项目摘要
辅助性T(Th)细胞是表达CD 4的T淋巴细胞,其分化成几个亚类以支持不同的免疫应答。
免疫反应。在Th亚群分化选择的多样性中,IL-17 A产生性炎症反应是Th亚群分化的一个重要因素。
Th 17细胞由于其相对高水平的固有可塑性而脱颖而出。事实上,这个子集
通常在粘膜免疫中对细菌和真菌起作用的T细胞可以容易地采用其他T细胞的特征,
当环境条件发生变化时,帮助器子集。虽然该特征在通信期间可能是有利的,
感染的清除,失调的Th 17细胞功能已经涉及许多自身免疫性疾病,
病症,包括炎症性肠病、多发性硬化症和风湿性关节炎。此外,委员会认为,
在炎性疾病的背景下表现出的Th 17细胞可塑性倾向于呈现Th 1样特征,例如
IFNg或T-bet的表达,其也与病理学增加相关。在我们目前资助的研究中,
我们鉴定了JunB-T-bet轴作为控制Th 17细胞谱系稳定性的调节网络的中心节点
相对于可塑性。虽然影响Th 17细胞身份和功能的转录程序的几种调节因子,
灵活性已被确定,但对三维基因组结构的调节因子知之甚少
它在细胞类型和状态之间存在差异,是基因调控的关键决定因素。因此,我们假设
谱系特异性因子对染色质确认的调节是控制CD 4 T细胞效应子的关键,
转换。在这里,我们建议全面评估染色质构型的动态变化
以及体内控制Th 17细胞效应子转化的顺式基因组元件。为此,在目标1中,我们
应用遗传命运作图小鼠模型、全局染色质构象分析和表观基因组分析
工具来表征小鼠模型中Th 17细胞可塑性期间的染色质循环动力学,
实验性自身免疫性脑脊髓炎(EAE)。我们将确定成环对Th 17细胞的贡献
通过评估染色质组织蛋白和谱系调节蛋白的作用,
转录因子在目标2中,我们计划确定控制Th 17细胞可塑性的顺式调节网络。
为此,我们将应用EAE中Th细胞的scATACseq分析来鉴定可塑性相关的顺式元件。我们
将使用新的体内高通量报告基因测定来验证候选物的活性和功能,
CRISPR/Cas9表观基因组筛选。这将确定新的调控网络、调控因子和基因靶点
对Th 17细胞效应器可塑性至关重要。总的来说,这项工作将填补知识上的一个重要空白
关于Th 17细胞的稳定性与可塑性的分子机制。
英文摘要
PROJECT SUMMARY
T helper (Th) cells are CD4-expressing T lymphocytes that diversify into several subclasses to support distinct
immune responses. Among the diversity of Th subset differentiation options, IL-17A-producing inflammatory
Th17 cells stand out as unique by virtue of their relatively high level of inherent plasticity. Indeed, this subset
that normally functions in mucosal immunity against bacteria and fungi can easily adopt features of other T
helper subsets when environmental conditions change. While this feature can be advantageous during the
clearance of an infection, dysregulated Th17 cell function has been implicated in numerous autoimmune
conditions, including Inflammatory Bowel Disease, Multiple Sclerosis, and Rheumatoid Arthritis. Moreover,
Th17 cell plasticity exhibited in the context of inflammatory disease tends to take on Th1-like traits, such as
expression of IFNg or T-bet, that are also associated with increased pathology. In our current funded studies,
we identified a JunB-T-bet axis as a central node in the regulatory network governing Th17 cell lineage stability
versus plasticity. While several regulators influencing the transcriptional program of Th17 cell identity and
flexibility have been identified, less is known about the regulators of the three-dimensional genome architecture
that differs between cell types and states and is a critical determinant of gene regulation. Thus, we hypothesize
that regulation of chromatin confirmation by lineage-specific factors is key to the control of CD4 T cell effector
conversions. Here, we propose to comprehensively evaluate the dynamic changes in chromatin configuration
and the cis genomic elements that govern Th17 cell effector conversions in vivo. To this end, in Aim 1, we will
apply genetic fate-mapping mouse models, global chromatin conformation assays, and epigenomic profiling
tools to characterize the chromatin looping dynamics during Th17 cell plasticity in a mouse model of
experimental autoimmune encephalomyelitis (EAE). We will determine the contribution of looping to Th17 cell
plastic conversion by assessing the role of both chromatin organizing proteins and lineage-regulating
transcription factors. In Aim 2, we plan to determine the cis regulatory network that governs Th17 cell plasticity.
For this, we will apply scATACseq profiling of Th cells in EAE to identify plasticity-associated cis elements. We
will validate candidates for activity and function using novel in vivo high throughput reporter assays and
CRISPR/Cas9 epigenomic screens. This will identify new regulatory networks, regulators, and gene targets
critical to Th17 cell effector plasticity. Taken together, the proposed work will fill an important gap in knowledge
concerning the molecular mechanism governing stability versus plasticity of Th17 cells.
期刊论文(0)
专著(0)
科研奖励(0)
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海外基金