DETERMINING THE ROLE OF THE REPLICATIVE HELICASE IN HUMAN NK CELL DEVELOPMENT
确定复制解旋酶在人类 NK 细胞发育中的作用
基本信息
- 批准号:10468048
- 负责人:
- 金额:$ 36.45万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2018
- 资助国家:美国
- 起止时间:2018-09-24 至 2023-08-31
- 项目状态:已结题
- 来源:
- 关键词:AffectAntiviral ResponseApoptosisBiologicalCD34 geneCDC45L geneCRISPR/Cas technologyCell CompartmentationCell CycleCell Cycle ArrestCell Cycle RegulationCell Differentiation processCell MaturationCell ProliferationCell divisionCell physiologyCellsCellular biologyCharacteristicsClinicalComplexDNADNA DamageDNA biosynthesisDataDefectDevelopmentDiseaseEffector CellFlow CytometryGene ExpressionGene Expression ProfileGene Expression ProfilingGenerationsGenesHealthHematopoietic Stem Cell TransplantationHematopoietic stem cellsHeterogeneityHomeostasisHumanImmuneImmune responseImmunologic Deficiency SyndromesImmunologicsImpairmentIn VitroLeadLightLymphocyteLymphocyte SubsetLymphoidLymphoid CellLyticMCM10 geneMCM4 geneMalignant NeoplasmsMediatingModelingMolecularMutationNatural Killer CellsNatureOutcomePathogenicityPathway interactionsPatientsPhasePhenotypePlayPrecursor Natural Killer CellPredispositionProcessProteinsRegulationReplication InitiationRoleSystemTestingTherapeuticTranslatingTransplantationTumor ImmunityViralVirus DiseasesWorkcell motilitycohortgraft vs host diseasehelicasehuman diseaseimmune reconstitutioninsightnovelperipheral bloodpreventresponsesingle cell analysissingle-cell RNA sequencingsuccesstool
项目摘要
PROJECT SUMMARY
This proposal builds upon exciting new paradigm defined by isolated human NK cell deficiency resulting from
hypomorphic mutations in multiple structural components of the eukaryotic DNA helicase. The discovery of
multiple patient cohorts with a strikingly similar NK cell phenotype, namely that of impaired terminal maturation
leading to susceptibility to severe viral infection and malignancy, underscores the impact of these mutations on
human NK cell development and function. Despite this compelling new insight driven by human disease, the
requirement for the DNA helicase complex specifically in NK cell function has not been defined. In the
proposed work, we will define this requirement in the context of NK cell differentiation and proliferation to make
important advances in both NK cell biology and human health.
Despite their documented requirement in determining the outcome and success of transplantation, NK
cell development and acquisition of function is poorly understood. A powerful tool in defining requirements for
human NK cell differentiation is the study of patients with monogenic causes of impaired NK cell maturation
leading to isolated NK cell deficiency (NKD). Using this approach, we and others have identified novel NKD
resulting from mutations in the CDC45-MCM-GINS DNA helicase complex and associated proteins. In the
proposed work, we will define the requirement for the CMG complex and, more broadly, proliferation and cell
division in human NK cell development. Specifically, we will 1) define the effect of CMG helicase mutations
on peripheral blood subset heterogeneity using single cell RNA sequencing and unbiased quantitative flow
cytometry. Furthermore, we have 2) developed a model for patient mutations that will allow us to dissect
the effect of these mutations on NK cell differentiation from earliest precursor to mature cell. We will
use this, combined with our validated in vitro NK cell differentiation system, to dissect the mechanism by which
hypomorphic CMG mutations affect human NK cell development and acquisition of lytic function. Finally, we
will 3) define the effect of CMG helicase mutations on the human NK cell antiviral response. Using
careful analysis of gene expression, phenotype and function, we will determine the timing and the nature of
developmental deregulation in NK cell developmental intermediates with hypomorphic replisome mutations.
These aims we will advance a novel new paradigm in human NK cell differentiation, namely the specific
requirement for proliferation and cell cycle control for NK cell terminal maturation. These studies have
significant clinical importance for understanding the differentiation of NK cells in the unique milieu following
hematopoietic stem cell transplant. Defining the role of proliferation in the generation of mature NK cell
effectors will enable the better control of these cells to prevent graft vs. host disease and promote their natural
anti-tumor immunity.
项目摘要
该建议建立在令人兴奋的新范式基础上,该范式由以下原因导致的孤立的人类NK细胞缺乏症定义:
真核DNA解旋酶的多个结构组分中的亚晶突变。的发现
多个患者队列具有惊人相似的NK细胞表型,即终末成熟受损
导致对严重病毒感染和恶性肿瘤的易感性,强调了这些突变对
人类NK细胞发育和功能。尽管这一引人注目的新见解是由人类疾病驱动的,
在NK细胞功能中对DNA解旋酶复合物的特异性要求尚未确定。在
建议的工作,我们将在NK细胞分化和增殖的背景下定义这一要求,
NK细胞生物学和人类健康的重要进展。
尽管他们在确定移植的结果和成功方面有记录的要求,
细胞发育和功能的获得知之甚少。一个定义需求的强大工具,
人类NK细胞分化是对具有NK细胞成熟受损的单基因原因的患者的研究
导致孤立的NK细胞缺乏症(NKD)。使用这种方法,我们和其他人已经确定了新的NKD
由CDC 45-MCM-GINS DNA解旋酶复合物和相关蛋白的突变引起。在
建议的工作,我们将定义CMG复合物的要求,更广泛地说,增殖和细胞
在人类NK细胞发育中的分裂。具体来说,我们将1)定义CMG解旋酶突变的影响
使用单细胞RNA测序和无偏定量流对外周血亚群异质性的研究
细胞仪此外,我们还建立了一个病人突变模型,
这些突变对NK细胞从最早的前体细胞分化为成熟细胞的影响。我们将
利用这一点,结合我们经过验证的体外NK细胞分化系统,来剖析其机制,
亚型CMG突变影响人NK细胞发育和溶解功能获得。最后我们
将3)确定CMG解旋酶突变对人NK细胞抗病毒应答的影响。使用
仔细分析基因表达、表型和功能,我们将确定其时机和性质
具有亚纯复制体突变的NK细胞发育中间体的发育失调。
这些目标,我们将提出一种新的人类NK细胞分化的新模式,即特异性的NK细胞分化。
NK细胞终末成熟需要增殖和细胞周期控制。这些研究
对于理解NK细胞在以下独特环境中的分化具有重要的临床意义:
造血干细胞移植确定增殖在成熟NK细胞生成中的作用
效应子将能够更好地控制这些细胞,以防止移植物抗宿主病,并促进它们的自然生长。
抗肿瘤免疫
项目成果
期刊论文数量(3)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Diversity of human NK cell developmental pathways defined by single-cell analyses.
通过单细胞分析定义的人类NK细胞发育途径的多样性。
- DOI:10.1016/j.coi.2021.11.001
- 发表时间:2022-03
- 期刊:
- 影响因子:7
- 作者:Seo S;Mace EM
- 通讯作者:Mace EM
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Emily Margaret Mace其他文献
Emily Margaret Mace的其他文献
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{{ truncateString('Emily Margaret Mace', 18)}}的其他基金
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- 批准号:
10735537 - 财政年份:2023
- 资助金额:
$ 36.45万 - 项目类别:
Generation of novel histoculture methods for studying human NK cell development
研究人类 NK 细胞发育的新型组织培养方法的产生
- 批准号:
10310513 - 财政年份:2020
- 资助金额:
$ 36.45万 - 项目类别:
DEFINING THE ROLE OF CELL MIGRATION IN HUMAN NK CELL DIFFERENTIATION
定义细胞迁移在人类 NK 细胞分化中的作用
- 批准号:
9897729 - 财政年份:2018
- 资助金额:
$ 36.45万 - 项目类别:
DEFINING THE ROLE OF CELL MIGRATION IN HUMAN NK CELL DIFFERENTIATION
定义细胞迁移在人类 NK 细胞分化中的作用
- 批准号:
10190802 - 财政年份:2018
- 资助金额:
$ 36.45万 - 项目类别:
DEFINING THE ROLE OF CELL MIGRATION IN HUMAN NK CELL DIFFERENTIATION
定义细胞迁移在人类 NK 细胞分化中的作用
- 批准号:
10410409 - 财政年份:2018
- 资助金额:
$ 36.45万 - 项目类别:
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确定复制解旋酶在人类 NK 细胞发育中的作用
- 批准号:
9790924 - 财政年份:2018
- 资助金额:
$ 36.45万 - 项目类别:
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