Regulation of adaptive immunity by the NOD-like receptor NLRP10

NOD 样受体 NLRP10 对适应性免疫的调节

基本信息

  • 批准号:
    9188793
  • 负责人:
  • 金额:
    $ 41.63万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2013
  • 资助国家:
    美国
  • 起止时间:
    2013-12-01 至 2018-11-30
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): The research outlined in the proposal aims to elucidate a fundamental pathway regulating dendritic cell induction of T cell sensitization to allergens in the lung. Work over the past 15 years has determined that mature pulmonary dendritic cells (DC) from the lung regulate type 2 CD4+ T cell (Th2) responses to allergens in asthma and that activation of pattern recognition receptors such as Toll-like receptors (TLRs) is a primary determinant of DC maturation driving sensitization. Although the early steps of TLR-induced DC maturation and the later steps of chemokine guided migration to draining lymph nodes are well characterized, relatively little is known about the intermediate step of DC detachment from inflamed tissues. We recently discovered a new innate immune pathway within the DC that specifically regulates its ability to egress from inflamed tissues while leaving the ret of the inflammatory and antigen presenting functions intact. NLRP10 is a member of the NOD-like receptor class of pattern recognition receptors and in its absence, DCs fail to traffic antige to lymph nodes and consequently CD4+ T cell priming is profoundly impaired. We will delineate how NLRP10 regulates dendritic cell movement, in exactly which type of DC and what aspects of lung immunity are impaired in the absence of NLRP10 through the following two specific aims. Aim 1) Identify NLRP10-dependent and - independent dendritic cell subsets in the lung and define their ability to activate CD4+ and CD8+ T cells. Preliminary data suggests that loss of NLRP10 only affects a subset of DCs (expressing the marker CD11b), which preferentially prime CD4+ but not CD8+ T cells. We hypothesize that paralysis of NLRP10-dependent DCs in the lung will result in tolerance rather than Th2 priming following aeroallergen exposure while leaving NLRP10-independndent DC priming of anti-viral CD8+ T cells intact. We will test this hypothesis in Aim 1 using in vivo aeroallergen sensitization models (Th2) and influenza infection (CD8+ T cell). NLRP10-deficient mice provide the only animal model in which the function of the migratory CD11b+ DC subset is specifically affected and therefore allows for the first time determination of the exact role of these DCs in pulmonary immune responses. Aim 2) Determine whether failed DC trafficking to lymph nodes is due to impaired DC detachment from lung extracellular matrix molecules. To define the molecular interactions regulating DC release from the lung we will develop matrices with recombinant matrix molecules to test NLRP10-deficient DC adhesion and migration in vitro; further we will block primary determinants of DC attachment to the lung parenchyma in vivo to overcome failed Th2 priming to aeroallergens in NLRP10-deficient mice. If loss of NLRP10 selectively abrogates DC-mediated CD4+ T cell priming to aeroallergens, then targeting this pathway might allow us to control the balance between sensitization and tolerance in allergic disease while potentially leaving protective CD8+ T cell immunity intact. Therefore our long-term goal following completion of these studies is to develop a DC-based approach to treat allergic disease through inhibition of NLRP10 pathways.
描述(由申请人提供):提案中概述的研究旨在阐明调节树突状细胞诱导T细胞对肺部过敏原致敏的基本途径。过去15年的工作已经确定,来自肺的成熟肺树突状细胞(DC)调节哮喘中2型CD 4 + T细胞(Th 2)对过敏原的应答,并且模式识别受体如Toll样受体(TLR)的激活是DC成熟驱动致敏的主要决定因素。尽管TLR诱导的DC成熟的早期步骤和趋化因子引导的向引流淋巴结的迁移的后期步骤被很好地表征,但是关于DC从发炎组织脱离的中间步骤相对知之甚少。我们最近在DC内发现了一种新的先天免疫途径,该途径特异性地调节其从炎症组织中排出的能力,同时保持炎症和抗原呈递功能的完整性。NLRP 10是模式识别受体中NOD样受体类别的成员,在其缺失的情况下,DC无法将抗原运输到淋巴结,因此CD 4 + T细胞启动作用严重受损。我们将描述NLRP 10如何调节树突状细胞的运动,确切地说,哪种类型的DC和肺免疫的哪些方面在NLRP 10的情况下受损,通过以下两个具体的目标。目的1)鉴定肺中NLRP 10依赖性和非依赖性树突状细胞亚群,并确定其激活CD 4+和CD 8 + T细胞的能力。初步数据表明,NLRP 10的缺失仅影响DC的一个亚群(表达标记物CD 11b),其优先引发CD 4 + T细胞而不是CD 8 + T细胞。我们假设肺中NLRP 10依赖性DC的麻痹将导致耐受性,而不是吸入过敏原暴露后的Th 2启动,同时保持抗病毒CD 8 + T细胞的NLRP 10非依赖性DC启动完整。我们将在目标1中使用体内空气变应原致敏模型(Th 2)和流感感染(CD 8 + T细胞)来检验这一假设。NLRP 10缺陷小鼠提供了唯一的动物模型,其中迁移性CD 11b + DC亚群的功能受到特异性影响,因此首次确定了这些DC在肺免疫应答中的确切作用。目的2)确定DC向淋巴结运输失败是否是由于DC从肺细胞外基质分子的脱离受损。为了确定调节DC从肺释放的分子相互作用,我们将开发具有重组基质分子的基质,以测试NLRP 10缺陷型DC体外粘附和迁移;此外,我们将在体内阻断DC附着于肺实质的主要决定因素,以克服NLRP 10缺陷型小鼠中Th 2对吸入性过敏原的致敏失败。如果NLRP 10的缺失选择性地消除DC介导的CD 4 + T细胞对空气过敏原的引发,那么靶向该途径可能使我们能够控制过敏性疾病中致敏和耐受之间的平衡,同时可能保持保护性CD 8 + T细胞免疫力不变。因此,在完成这些研究后,我们的长期目标是开发一种基于DC的方法,通过抑制NLRP 10途径治疗过敏性疾病。

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 }}

Stephanie Caroline Eisenbarth其他文献

Stephanie Caroline Eisenbarth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('Stephanie Caroline Eisenbarth', 18)}}的其他基金

Determinants of oral anaphylaxis to food
口腔食物过敏的决定因素
  • 批准号:
    10586739
  • 财政年份:
    2023
  • 资助金额:
    $ 41.63万
  • 项目类别:
The adaptive immune response to food antigens in the gut
肠道内对食物抗原的适应性免疫反应
  • 批准号:
    10455274
  • 财政年份:
    2021
  • 资助金额:
    $ 41.63万
  • 项目类别:
Immune mechanisms regulating allergy
调节过敏的免疫机制
  • 批准号:
    10197629
  • 财政年份:
    2018
  • 资助金额:
    $ 41.63万
  • 项目类别:
Immune mechanisms regulating allergy
调节过敏的免疫机制
  • 批准号:
    10461080
  • 财政年份:
    2018
  • 资助金额:
    $ 41.63万
  • 项目类别:
Immune mechanisms regulating allergy
调节过敏的免疫机制
  • 批准号:
    9980783
  • 财政年份:
    2018
  • 资助金额:
    $ 41.63万
  • 项目类别:
Immune mechanisms regulating allergy
调节过敏的免疫机制
  • 批准号:
    10548673
  • 财政年份:
    2018
  • 资助金额:
    $ 41.63万
  • 项目类别:
Immune mechanisms regulating allergy
调节过敏的免疫机制
  • 批准号:
    10240308
  • 财政年份:
    2018
  • 资助金额:
    $ 41.63万
  • 项目类别:
Innate Immune Receptors that Promote RBC Alloimmunization
促进红细胞同种免疫的先天免疫受体
  • 批准号:
    10192794
  • 财政年份:
    2017
  • 资助金额:
    $ 41.63万
  • 项目类别:
Regulation of adaptive immunity by the NOD-like receptor NLRP10
NOD 样受体 NLRP10 对适应性免疫的调节
  • 批准号:
    8612109
  • 财政年份:
    2013
  • 资助金额:
    $ 41.63万
  • 项目类别:
Role of the Nlrp3 Inflammasome in Adaptive Immunity
Nlrp3 炎症小体在适应性免疫中的作用
  • 批准号:
    8081119
  • 财政年份:
    2010
  • 资助金额:
    $ 41.63万
  • 项目类别:

相似海外基金

How Does Particle Material Properties Insoluble and Partially Soluble Affect Sensory Perception Of Fat based Products
不溶性和部分可溶的颗粒材料特性如何影响脂肪基产品的感官知觉
  • 批准号:
    BB/Z514391/1
  • 财政年份:
    2024
  • 资助金额:
    $ 41.63万
  • 项目类别:
    Training Grant
BRC-BIO: Establishing Astrangia poculata as a study system to understand how multi-partner symbiotic interactions affect pathogen response in cnidarians
BRC-BIO:建立 Astrangia poculata 作为研究系统,以了解多伙伴共生相互作用如何影响刺胞动物的病原体反应
  • 批准号:
    2312555
  • 财政年份:
    2024
  • 资助金额:
    $ 41.63万
  • 项目类别:
    Standard Grant
RII Track-4:NSF: From the Ground Up to the Air Above Coastal Dunes: How Groundwater and Evaporation Affect the Mechanism of Wind Erosion
RII Track-4:NSF:从地面到沿海沙丘上方的空气:地下水和蒸发如何影响风蚀机制
  • 批准号:
    2327346
  • 财政年份:
    2024
  • 资助金额:
    $ 41.63万
  • 项目类别:
    Standard Grant
Graduating in Austerity: Do Welfare Cuts Affect the Career Path of University Students?
紧缩毕业:福利削减会影响大学生的职业道路吗?
  • 批准号:
    ES/Z502595/1
  • 财政年份:
    2024
  • 资助金额:
    $ 41.63万
  • 项目类别:
    Fellowship
感性個人差指標 Affect-X の構築とビスポークAIサービスの基盤確立
建立个人敏感度指数 Affect-X 并为定制人工智能服务奠定基础
  • 批准号:
    23K24936
  • 财政年份:
    2024
  • 资助金额:
    $ 41.63万
  • 项目类别:
    Grant-in-Aid for Scientific Research (B)
Insecure lives and the policy disconnect: How multiple insecurities affect Levelling Up and what joined-up policy can do to help
不安全的生活和政策脱节:多种不安全因素如何影响升级以及联合政策可以提供哪些帮助
  • 批准号:
    ES/Z000149/1
  • 财政年份:
    2024
  • 资助金额:
    $ 41.63万
  • 项目类别:
    Research Grant
How does metal binding affect the function of proteins targeted by a devastating pathogen of cereal crops?
金属结合如何影响谷类作物毁灭性病原体靶向的蛋白质的功能?
  • 批准号:
    2901648
  • 财政年份:
    2024
  • 资助金额:
    $ 41.63万
  • 项目类别:
    Studentship
Investigating how double-negative T cells affect anti-leukemic and GvHD-inducing activities of conventional T cells
研究双阴性 T 细胞如何影响传统 T 细胞的抗白血病和 GvHD 诱导活性
  • 批准号:
    488039
  • 财政年份:
    2023
  • 资助金额:
    $ 41.63万
  • 项目类别:
    Operating Grants
New Tendencies of French Film Theory: Representation, Body, Affect
法国电影理论新动向:再现、身体、情感
  • 批准号:
    23K00129
  • 财政年份:
    2023
  • 资助金额:
    $ 41.63万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
The Protruding Void: Mystical Affect in Samuel Beckett's Prose
突出的虚空:塞缪尔·贝克特散文中的神秘影响
  • 批准号:
    2883985
  • 财政年份:
    2023
  • 资助金额:
    $ 41.63万
  • 项目类别:
    Studentship
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了