IL-4-activated macrophages: Contribution to allergic lung inflammation linked to viral infection

IL-4 激活的巨噬细胞:导致与病毒感染相关的过敏性肺部炎症

基本信息

  • 批准号:
    10532357
  • 负责人:
  • 金额:
    $ 61.06万
  • 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:
    2019-01-03 至 2024-12-31
  • 项目状态:
    已结题

项目摘要

SUMMARY It is now recognized that infection of genetically susceptible individuals with certain respiratory viruses, including human rhinovirus (HRV) and respiratory syncytial virus (RSV), during infancy or early childhood leads to an increased risk of subsequent development of allergic asthma. Survivors of preterm birth, with and without the complication bronchopulmonary dysplasia (BPD), exhibit increased susceptibility to viral infection and greater risk of developing childhood-onset asthma than term infants. In addition, infection of children with allergic asthma with these viruses can severely exacerbate ongoing disease. Despite the recognition of this relationship, the mechanism linking viral infection and susceptibility to and severity of allergic lung inflammation is not known representing a critical unmet need. We have shown that viral infection induces the IL-4Ra-dependent, alternative activation of macrophages (Mf) referred to as “M2” in lungs of mice that remain long after virus is cleared (~90 days after infection). Fur- thermore, we showed that allergens induce M2 in the lung and that M2 actively mediate enhanced allergic in- flammation. Adoptive transfer of highly purified Mf that express IL-4Ra into IL-4Ra-/- mice resulted in the differ- entiation of M2 in the lung that mitigated virus-induced pro-inflammatory pathology, as part of their repair func- tion. However, they produced Th2-promoting cytokines and actively promoted allergen-induced, Th2-driven al- lergic inflammation associated with asthma. Recent studies demonstrated that M2 Mf polarization is associated with normal alveolar development, and increased M2 polarization protected against hyperoxia-induced lung in- jury in neonatal mice. Based on our recent publications and additional preliminary data described in this appli- cation, we propose the novel hypothesis that enhanced responsiveness to allergen exposure that occurs after viral infection of young mice is in part mediated by long-lived M2. We further propose that virus-induced exacer- bation of ongoing allergic disease is mediated by M2. To test this hypothesis, we will complete the following specific aims: 1) to determine the mechanism for M2 maintenance between virus and allergen exposure; 2) to analyze the specific role of Mfs on the virus-induced enhanced responses to allergen and virus-induced exac- erbation; and 3) to characterize the contribution M2 to enhanced susceptibility of neonates to virus-induced inception of allergic inflammation in vivo. This project will benefit from the expertise and oversight of the 3 PIs. At the conclusion of these studies, we expect to have determined the mechanism by which viral infection leads to development of long-lived M2 that enhance the development of asthma later in life. They will determine whether alterations in lung M2 formation during lung maturation lead to virus-enhanced asthma, thus providing a potential therapeutic target.
概括 现在人们认识到,遗传易感个体感染某些呼吸道病毒, 包括人类鼻病毒 (HRV) 和呼吸道合胞病毒 (RSV),在婴儿期或幼儿期导致 随后发生过敏性哮喘的风险增加。早产幸存者,无论是否患有早产 并发症支气管肺发育不良(BPD),表现出对病毒感染的易感性增加,并且 患儿童期哮喘的风险高于足月婴儿。另外,感染过敏性哮喘的儿童 这些病毒可能会严重加剧正在发生的疾病。尽管承认这种关系, 病毒感染与过敏性肺部炎症的易感性和严重程度之间的联系机制尚不清楚 代表未满足的关键需求。 我们已经证明,病毒感染会诱导巨噬细胞依赖 IL-4Ra 的选择性激活 (Mf) 被称为小鼠肺部的“M2”,在病毒被清除后很长时间(感染后约 90 天)仍保留。毛皮- 此外,我们发现过敏原在肺部诱导 M2,并且 M2 主动介导增强的过敏反应。 燃烧。将表达 IL-4Ra 的高度纯化的 Mf 过继转移至 IL-4Ra-/- 小鼠中导致了不同的结果: M2 在肺部的作用减轻了病毒诱导的促炎病理,作为其修复功能的一部分 。然而,它们产生促进 Th2 的细胞因子,并积极促进过敏原诱导的、Th2 驱动的 al- 与哮喘相关的过敏性炎症。最近的研究表明 M2 Mf 极化与 肺泡发育正常,M2 极化增强可防止高氧诱导的肺损伤 新生小鼠陪审团。根据我们最近发表的出版物和本申请中描述的其他初步数据, 阳离子,我们提出了一个新的假设,即增强对过敏原暴露后发生的反应 幼鼠的病毒感染部分是由长寿的 M2 介导的。我们进一步提出病毒诱导的加重- 持续过敏性疾病的缓解是由 M2 介导的。为了检验这个假设,我们将完成以下任务 具体目标:1)确定病毒和过敏原暴露之间M2维持的机制; 2)到 分析Mfs对病毒引起的过敏原增强反应和病毒引起的exac-的具体作用 解散; 3) 表征 M2 对新生儿病毒诱发的易感性增强的贡献 体内过敏性炎症的开始。 该项目将受益于 3 位 PI 的专业知识和监督。在这些研究的结论中, 我们希望能够确定病毒感染导致长寿命 M2 发育的机制 促进晚年哮喘的发展。他们将确定肺 M2 形成是否发生改变 在肺成熟期间导致病毒增强的哮喘,从而提供了潜在的治疗靶点。

项目成果

期刊论文数量(2)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Perspectives and potential approaches for targeting neuropilin 1 in SARS-CoV-2 infection.
Recent advances in understanding the role of IL-4 signaling.
  • DOI:
    10.12703/r/10-71
  • 发表时间:
    2021
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Keegan AD;Leonard WJ;Zhu J
  • 通讯作者:
    Zhu J
{{ 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 }}

Achsah D. Keegan其他文献

Achsah D. Keegan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('Achsah D. Keegan', 18)}}的其他基金

IL-4-activated macrophages: Contribution to allergic lung inflammation linked to viral infection
IL-4 激活的巨噬细胞:导致与病毒感染相关的过敏性肺部炎症
  • 批准号:
    10320382
  • 财政年份:
    2019
  • 资助金额:
    $ 61.06万
  • 项目类别:
Role of Semaphorin 4A in Allergic Inflammation
Semaphorin 4A 在过敏性炎症中的作用
  • 批准号:
    9973137
  • 财政年份:
    2018
  • 资助金额:
    $ 61.06万
  • 项目类别:
Role of Semaphorin 4A in Allergic Inflammation
Semaphorin 4A 在过敏性炎症中的作用
  • 批准号:
    10455489
  • 财政年份:
    2018
  • 资助金额:
    $ 61.06万
  • 项目类别:
Role of Semaphorin 4A in Allergic Inflammation
Semaphorin 4A 在过敏性炎症中的作用
  • 批准号:
    10212219
  • 财政年份:
    2018
  • 资助金额:
    $ 61.06万
  • 项目类别:
Role of Semaphorin 4A in Allergic Inflammation
Semaphorin 4A 在过敏性炎症中的作用
  • 批准号:
    9753901
  • 财政年份:
    2018
  • 资助金额:
    $ 61.06万
  • 项目类别:
Insulin Receptor Substrate Signaling in Pulmonary Hypertension
肺动脉高压中的胰岛素受体底物信号转导
  • 批准号:
    10305606
  • 财政年份:
    2017
  • 资助金额:
    $ 61.06万
  • 项目类别:
Insulin Receptor Substrate Signaling in Pulmonary Hypertension
肺动脉高压中的胰岛素受体底物信号转导
  • 批准号:
    10089467
  • 财政年份:
    2017
  • 资助金额:
    $ 61.06万
  • 项目类别:
Regulation of Macrophage Activation by House Dust Mite
屋尘螨对巨噬细胞激活的调节
  • 批准号:
    8541976
  • 财政年份:
    2013
  • 资助金额:
    $ 61.06万
  • 项目类别:
Regulation of Macrophage Activation by House Dust Mite
屋尘螨对巨噬细胞激活的调节
  • 批准号:
    8670552
  • 财政年份:
    2013
  • 资助金额:
    $ 61.06万
  • 项目类别:
Regulation of Macrophage Activation by House Dust Mite
屋尘螨对巨噬细胞激活的调节
  • 批准号:
    9898273
  • 财政年份:
    2013
  • 资助金额:
    $ 61.06万
  • 项目类别:

相似海外基金

Co-designing a lifestyle, stop-vaping intervention for ex-smoking, adult vapers (CLOVER study)
为戒烟的成年电子烟使用者共同设计生活方式、戒烟干预措施(CLOVER 研究)
  • 批准号:
    MR/Z503605/1
  • 财政年份:
    2024
  • 资助金额:
    $ 61.06万
  • 项目类别:
    Research Grant
Early Life Antecedents Predicting Adult Daily Affective Reactivity to Stress
早期生活经历预测成人对压力的日常情感反应
  • 批准号:
    2336167
  • 财政年份:
    2024
  • 资助金额:
    $ 61.06万
  • 项目类别:
    Standard Grant
RAPID: Affective Mechanisms of Adjustment in Diverse Emerging Adult Student Communities Before, During, and Beyond the COVID-19 Pandemic
RAPID:COVID-19 大流行之前、期间和之后不同新兴成人学生社区的情感调整机制
  • 批准号:
    2402691
  • 财政年份:
    2024
  • 资助金额:
    $ 61.06万
  • 项目类别:
    Standard Grant
Elucidation of Adult Newt Cells Regulating the ZRS enhancer during Limb Regeneration
阐明成体蝾螈细胞在肢体再生过程中调节 ZRS 增强子
  • 批准号:
    24K12150
  • 财政年份:
    2024
  • 资助金额:
    $ 61.06万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Migrant Youth and the Sociolegal Construction of Child and Adult Categories
流动青年与儿童和成人类别的社会法律建构
  • 批准号:
    2341428
  • 财政年份:
    2024
  • 资助金额:
    $ 61.06万
  • 项目类别:
    Standard Grant
Understanding how platelets mediate new neuron formation in the adult brain
了解血小板如何介导成人大脑中新神经元的形成
  • 批准号:
    DE240100561
  • 财政年份:
    2024
  • 资助金额:
    $ 61.06万
  • 项目类别:
    Discovery Early Career Researcher Award
RUI: Evaluation of Neurotrophic-Like properties of Spaetzle-Toll Signaling in the Developing and Adult Cricket CNS
RUI:评估发育中和成年蟋蟀中枢神经系统中 Spaetzle-Toll 信号传导的神经营养样特性
  • 批准号:
    2230829
  • 财政年份:
    2023
  • 资助金额:
    $ 61.06万
  • 项目类别:
    Standard Grant
Usefulness of a question prompt sheet for onco-fertility in adolescent and young adult patients under 25 years old.
问题提示表对于 25 岁以下青少年和年轻成年患者的肿瘤生育力的有用性。
  • 批准号:
    23K09542
  • 财政年份:
    2023
  • 资助金额:
    $ 61.06万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Identification of new specific molecules associated with right ventricular dysfunction in adult patients with congenital heart disease
鉴定与成年先天性心脏病患者右心室功能障碍相关的新特异性分子
  • 批准号:
    23K07552
  • 财政年份:
    2023
  • 资助金额:
    $ 61.06万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Issue identifications and model developments in transitional care for patients with adult congenital heart disease.
成人先天性心脏病患者过渡护理的问题识别和模型开发。
  • 批准号:
    23K07559
  • 财政年份:
    2023
  • 资助金额:
    $ 61.06万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了