Sex Differences in NK Cells Mediated by X-linked UTX
X连锁UTX介导的NK细胞性别差异
基本信息
- 批准号:10750843
- 负责人:
- 金额:$ 65.23万
- 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:2023-07-07 至 2028-06-30
- 项目状态:未结题
- 来源:
- 关键词:AblationAntiviral ResponseApoptosisApoptoticBCL2 geneBindingBiological AssayCRISPR/Cas technologyCell CountCell MaturationCell physiologyCell-Mediated CytolysisCellsChromatinChromatin Remodeling FactorCytomegalovirusCytomegalovirus InfectionsDataDevelopmentDiseaseDisparityEP300 geneEffector CellEpigenetic ProcessFemaleGene ExpressionGenesGenetic TranscriptionGenomicsGonadal HormonesGranzymeHealthHomeostasisHormonesHumanImmuneImmune responseImmunotherapyImpairmentIn VitroInflammatoryInterferon Type IIInterventionKnowledgeLinkLymphocyteMammalsMediatingMethyltransferaseMolecularMurid herpesvirus 1MusNatural Killer CellsOutcomePhenocopyPositioning AttributePredispositionProductionRegulationResistanceRoleSamplingSex BiasSex ChromosomesSex DifferencesSystemTestingViralViral CancerVirus DiseasesX ChromosomeX Inactivationantiviral immunitycell typecytokinecytotoxiccytotoxicitydifferential expressionepigenomic profilingfitnessgenomic locushistone demethylaseimproved outcomein vivoinsightmalemouse modelnew therapeutic targetp300/CBP-Associated Factorperforinpersonalized therapeuticprogramsrecruitresponsesexsexual dimorphism
项目摘要
PROJECT SUMMARY/ABSTRACT
Viral infection outcomes are sex-biased, with males generally more susceptible to human cytomegalovirus
(HCMV) and other viral infections compared to females. These differences may reflect sexual dimorphism in
immune cell composition and function. As such, it is surprising that numbers of natural killer (NK) cells, a first
line of defense against HCMV, are increased in males compared to females. Here we show in mouse models
and human samples that while males harbor increased NK cell numbers, they produce less IFN-γ, a critical pro-
inflammatory cytokine for NK-mediated anti-viral responses. This difference is not due to divergent levels of
gonadal hormones, since these differences are still present in gonadectomized mice. Instead, a screen for X
chromosome genes that escape inactivation and demonstrate sexually dimorphic expression in NK cells
identified UTX, an epigenetic regulator that alters transcriptional programs through reorganization of chromatin.
NK cell-specific UTX deletion phenocopies multiple features of male NK cells, which include increased NK
numbers and reduced IFN-γ production. Thus, we hypothesize that NK cell sex differences can be attributed to
differential expression of X-linked UTX, which reorganizes chromatin at loci important in NK cell fitness and
function. In Aim 1, we will define UTX-mediated temporal control of NK cell numbers and determine whether
differences in cellular fitness underlie differences in NK cell homeostasis in males compared to females. In Aim
2, we will delineate UTX’s role in promoting NK cell cytotoxic activity and whether lower UTX levels in male NK
cells also impairs their cytotoxic capacity. In Aim 3, we will delineate molecular mechanisms by which UTX
controls chromatin accessibility and gene expression at loci important for NK cell homeostasis and function.
Knowledge gained from completion of these studies will contribute to our basic understanding of sex differences
in anti-viral responses and NK cells. A deeper understanding of sex differences will benefit human health overall
by revealing new targets for immunotherapy and guiding interventions for optimizing anti-viral immunity.
项目总结/摘要
病毒感染的结果存在性别偏见,男性通常更容易感染人类巨细胞病毒
(HCMV)和其他病毒感染与女性相比。这些差异可能反映了性别的二型性,
免疫细胞组成和功能。因此,令人惊讶的是,自然杀伤(NK)细胞的数量,第一个
与女性相比,男性的HCMV防御线增加。这里我们展示了小鼠模型
和人类样本,虽然男性拥有增加的NK细胞数量,他们产生较少的IFN-γ,一个关键的亲,
用于NK介导的抗病毒应答的炎性细胞因子。这种差异并不是因为
性腺激素,因为这些差异仍然存在于性腺切除小鼠。相反,X的屏幕
在NK细胞中逃避失活并显示性二态表达的染色体基因
鉴定了UTX,一种通过染色质重组改变转录程序的表观遗传调节因子。
NK细胞特异性UTX缺失表型复制了男性NK细胞的多种特征,包括NK细胞的增加。
减少IFN-γ的产生。因此,我们假设NK细胞的性别差异可以归因于
X连锁UTX的差异表达,其在NK细胞适应性中重要的位点重组染色质,
功能在目标1中,我们将定义UTX介导的NK细胞数量的时间控制,并确定是否
细胞适应性的差异是男性与女性相比NK细胞稳态差异的基础。在Aim中
2、探讨UTX在促进NK细胞杀伤活性中的作用,以及降低男性NK细胞中UTX水平是否会影响NK细胞的杀伤活性。
细胞也损害其细胞毒性能力。在目标3中,我们将描述UTX
控制对NK细胞稳态和功能重要的基因座处的染色质可及性和基因表达。
从这些研究中获得的知识将有助于我们对性别差异的基本理解
抗病毒反应和NK细胞。更深入地了解性别差异将有利于人类的整体健康
通过揭示免疫治疗的新靶点和指导优化抗病毒免疫的干预措施。
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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Timothy E O'Sullivan其他文献
Timothy E O'Sullivan的其他文献
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{{ truncateString('Timothy E O'Sullivan', 18)}}的其他基金
Transcriptional mechanisms of natural killer cell responses during mouse cytomegalovirus infection
小鼠巨细胞病毒感染期间自然杀伤细胞反应的转录机制
- 批准号:
10382356 - 财政年份:2019
- 资助金额:
$ 65.23万 - 项目类别:
Transcriptional mechanisms of natural killer cell responses during mouse cytomegalovirus infection
小鼠巨细胞病毒感染期间自然杀伤细胞反应的转录机制
- 批准号:
10596995 - 财政年份:2019
- 资助金额:
$ 65.23万 - 项目类别:
Transcriptional mechanisms of natural killer cell responses during mouse cytomegalovirus infection
小鼠巨细胞病毒感染期间自然杀伤细胞反应的转录机制
- 批准号:
9926225 - 财政年份:2019
- 资助金额:
$ 65.23万 - 项目类别:
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