Uncover the new subsets of epidermal Langerhans cells

发现表皮朗格汉斯细胞的新亚群

基本信息

  • 批准号:
    9912418
  • 负责人:
  • 金额:
    $ 37.63万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2019
  • 资助国家:
    美国
  • 起止时间:
    2019-09-17 至 2021-08-31
  • 项目状态:
    已结题

项目摘要

PROJECT SUMMARY Langerhans cells (LCs) are skin-resident dendritic cells (DCs) expressing the C-type lectin Langerin (CD207) that mediate both adaptive immunity and immune tolerance in skin and are involved in various types of skin diseases. Adult LCs are originated from embryonic yolk-sac-derived macrophages and fetal liver monocytes in the steady state. Interestingly, LCs could also be derived from the bone marrow or peripheral monocytes and repopulate the skin under inflammatory conditions. However, due to the lack of molecular profiles at individual LC level, a significant gap remains in our understanding on how a single CD207+ epidermal LC population can induce both immunity and tolerance. Fortunately, new technologies such as the single-cell RNA-sequencing (scRNA-seq) can evaluate cell-to-cell transcriptomic variation, while the single-cell assay for transposase- accessible chromatin using sequencing (scATAC-seq) can assess the epigenomic heterogeneity at single-cell resolution in an unbiased manner. Recently, we identified two major LC subsets in mice, ATF3+Bal2a1b- (mLC1) and ATF3-Bal2a1b+(mLC2) subsets, and three major LC subsets in human including ATF3+ (hLC1) subset using scRNA-seq. We also found in ATF3 knockout mice that lack of ATF3 enhances LC maturation and promotes LCs-induced Th1 and Th17 cell differentiation suggesting immune suppressive function induced by ATF3+LC1. Hence, these preliminary data support our hypothesis that LCs are heterogeneous consisting of distinct subsets with different immune functions. Our objective is to use single-cell analysis platforms plus the LC fate-mapping and mutation mouse models to further validate this. We will pursue two Specific Aims in the R61 phase: Aim 1) Characterize the gene signatures and regulatory elements of mLC1 and mLC2 by profiling LCs during embryonic, young, and aging development at steady-state and repopulated LCs at inflamed state using scRNA-seq and scATAC-seq; Aim 2) Generate ATF3negEGFP reporter mice to fate-map ATF3+LC1 embryonic development and the dynamic change of ATF3+LC1 and ATF3-LC2 subset at steady state during adult and aging development and at inflammatory state and functionally characterize LC subsets in vitro by sorting ATF3EGFP+ LC1 and ATF3- LC2 cells and rederiving ATF3.loxp mice, which will be crossed with hLangerin-Cre mice to generate LC- specific/time-induced ATF3KO for in vivo functional study. In the R33 phase, we will pursue the following Specific Aim: Aim 3) Functionally characterize ATF3+LC1 subset in vivo using LC-specific ATF3 deletion hLCcre.ATF3KO mice to evaluate the potential immune regulation function of ATF3+LC1 subset in the different disease models, including autoimmune vitiligo, melanoma, and fungi infection models. Our work will uncover the mystery of LC subsets with their specific functions, which will provide new insights into the biology of LCs and lead to the development of LC-based intervention strategies for skin diseases.
项目摘要 朗格汉斯细胞(LC)是皮肤驻留的树突状细胞(DC),表达C型凝集素朗格林(CD 207) 其介导皮肤中的适应性免疫和免疫耐受,并涉及各种类型的皮肤 疾病成人LC来源于胚胎卵黄囊来源的巨噬细胞和胎肝单核细胞, 稳定状态有趣的是,LC也可以来源于骨髓或外周单核细胞, 在炎症条件下重新填充皮肤。然而,由于缺乏个体的分子特征, LC水平,在我们理解单个CD 207+表皮LC群体如何 诱导免疫和耐受。幸运的是,新技术,如单细胞RNA测序, (scRNA-seq)可以评估细胞间转录组变异,而转座酶-RNA的单细胞测定法可以评估细胞间转录组变异。 使用测序的可接近染色质(scATAC-seq)可以评估单细胞中的表观基因组异质性, 以公正的方式解决问题。最近,我们在小鼠中鉴定了两种主要的LC亚群,ATF 3 + Bal 2a 1b-(mLC 1)。 和ATF 3-Bal 2a 1b+(mLC 2)亚群,以及包括ATF 3+(hLC 1)亚群在内的人中的三种主要LC亚群, scRNA-seq.我们还发现,在ATF 3基因敲除小鼠中,缺乏ATF 3可增强LC成熟, LC诱导的Th 1和Th 17细胞分化表明ATF 3 + LC 1诱导的免疫抑制功能。 因此,这些初步数据支持我们的假设,即LC是由不同的子集组成的异质性 不同的免疫功能。我们的目标是使用单细胞分析平台加上LC命运图 和突变小鼠模型来进一步验证这一点。我们将在R61阶段实现两个具体目标: 通过分析胚胎期间的LC来表征mLC 1和mLC 2的基因特征和调控元件, 在稳态下的年轻和老化发育和在发炎状态下的再增殖LC, scATAC-seq;目的2)产生ATF 3 + EGFP报告小鼠以对ATF 3 + LC 1胚胎发育进行命运图谱绘制, ATF 3 + LC 1和ATF 3-LC 2亚群在成年和衰老过程中稳态动态变化 并通过分选ATF 3 EGFP + LC 1和ATF 3-EGFP + LC 1在体外功能上表征LC亚群。 LC 2细胞和再衍生的ATF3.loxp小鼠,其将与hLangerin-Cre小鼠杂交以产生LC-1细胞。 特异性/时间诱导的ATF 3 KO用于体内功能研究。在R33阶段,我们将追求以下具体目标: 目的:目的3)使用LC特异性ATF 3缺失hLCcre.ATF3KO在体内功能表征ATF 3 + LC 1亚群 评价ATF 3 + LC 1亚群在不同疾病模型中的潜在免疫调节功能, 包括自身免疫性白癜风、黑素瘤和真菌感染模型。我们的工作将揭开LC的神秘面纱 亚群及其特定功能,这将为LC的生物学提供新的见解,并导致 开发基于LC的皮肤病干预策略。

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)

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

Indra Adrianto其他文献

Indra Adrianto的其他文献

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

{{ truncateString('Indra Adrianto', 18)}}的其他基金

Genetic risk of hidradenitis suppurativa in African Americans
非裔美国人化脓性汗腺炎的遗传风险
  • 批准号:
    10549738
  • 财政年份:
    2022
  • 资助金额:
    $ 37.63万
  • 项目类别:
Genetic risk of hidradenitis suppurativa in African Americans
非裔美国人化脓性汗腺炎的遗传风险
  • 批准号:
    10703531
  • 财政年份:
    2022
  • 资助金额:
    $ 37.63万
  • 项目类别:
Genetic risk of hidradenitis suppurativa in African Americans
非裔美国人化脓性汗腺炎的遗传风险
  • 批准号:
    10372465
  • 财政年份:
    2022
  • 资助金额:
    $ 37.63万
  • 项目类别:
Uncover the new subsets of epidermal Langerhans cells
发现表皮朗格汉斯细胞的新亚群
  • 批准号:
    10464035
  • 财政年份:
    2019
  • 资助金额:
    $ 37.63万
  • 项目类别:
Uncover the new subsets of epidermal Langerhans cells
发现表皮朗格汉斯细胞的新亚群
  • 批准号:
    10020173
  • 财政年份:
    2019
  • 资助金额:
    $ 37.63万
  • 项目类别:

相似海外基金

Interplay between Aging and Tubulin Posttranslational Modifications
衰老与微管蛋白翻译后修饰之间的相互作用
  • 批准号:
    24K18114
  • 财政年份:
    2024
  • 资助金额:
    $ 37.63万
  • 项目类别:
    Grant-in-Aid for Early-Career Scientists
EMNANDI: Advanced Characterisation and Aging of Compostable Bioplastics for Automotive Applications
EMNANDI:汽车应用可堆肥生物塑料的高级表征和老化
  • 批准号:
    10089306
  • 财政年份:
    2024
  • 资助金额:
    $ 37.63万
  • 项目类别:
    Collaborative R&D
The Canadian Brain Health and Cognitive Impairment in Aging Knowledge Mobilization Hub: Sharing Stories of Research
加拿大大脑健康和老龄化认知障碍知识动员中心:分享研究故事
  • 批准号:
    498288
  • 财政年份:
    2024
  • 资助金额:
    $ 37.63万
  • 项目类别:
    Operating Grants
Baycrest Academy for Research and Education Summer Program in Aging (SPA): Strengthening research competencies, cultivating empathy, building interprofessional networks and skills, and fostering innovation among the next generation of healthcare workers t
Baycrest Academy for Research and Education Summer Program in Aging (SPA):加强研究能力,培养同理心,建立跨专业网络和技能,并促进下一代医疗保健工作者的创新
  • 批准号:
    498310
  • 财政年份:
    2024
  • 资助金额:
    $ 37.63万
  • 项目类别:
    Operating Grants
関節リウマチ患者のSuccessful Agingに向けたフレイル予防対策の構築
类风湿性关节炎患者成功老龄化的衰弱预防措施的建立
  • 批准号:
    23K20339
  • 财政年份:
    2024
  • 资助金额:
    $ 37.63万
  • 项目类别:
    Grant-in-Aid for Scientific Research (B)
Life course pathways in healthy aging and wellbeing
健康老龄化和福祉的生命历程路径
  • 批准号:
    2740736
  • 财政年份:
    2024
  • 资助金额:
    $ 37.63万
  • 项目类别:
    Studentship
NSF PRFB FY 2023: Connecting physiological and cellular aging to individual quality in a long-lived free-living mammal.
NSF PRFB 2023 财年:将生理和细胞衰老与长寿自由生活哺乳动物的个体质量联系起来。
  • 批准号:
    2305890
  • 财政年份:
    2024
  • 资助金额:
    $ 37.63万
  • 项目类别:
    Fellowship Award
I-Corps: Aging in Place with Artificial Intelligence-Powered Augmented Reality
I-Corps:利用人工智能驱动的增强现实实现原地老龄化
  • 批准号:
    2406592
  • 财政年份:
    2024
  • 资助金额:
    $ 37.63万
  • 项目类别:
    Standard Grant
McGill-MOBILHUB: Mobilization Hub for Knowledge, Education, and Artificial Intelligence/Deep Learning on Brain Health and Cognitive Impairment in Aging.
McGill-MOBILHUB:脑健康和衰老认知障碍的知识、教育和人工智能/深度学习动员中心。
  • 批准号:
    498278
  • 财政年份:
    2024
  • 资助金额:
    $ 37.63万
  • 项目类别:
    Operating Grants
Welfare Enhancing Fiscal and Monetary Policies for Aging Societies
促进老龄化社会福利的财政和货币政策
  • 批准号:
    24K04938
  • 财政年份:
    2024
  • 资助金额:
    $ 37.63万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了