Molecular and Cellular Dissection of miRNAs in Controlling Allergic Airway Inflammation in Mice
miRNA 在控制小鼠过敏性气道炎症中的分子和细胞解析
基本信息
- 批准号:10012111
- 负责人:
- 金额:--
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-07-01 至 2024-06-30
- 项目状态:已结题
- 来源:
- 关键词:AddressAffectAirway DiseaseAllergensAllergicAllergic DiseaseAllergic inflammationAntifungal AgentsAntigen-Presenting CellsAntigensAspergillus nigerAsthmaC-Type LectinsCD11c AntigensCD4 Positive T LymphocytesCellsChronicComplexDendritic CellsDendritic cell activationDetectionDevelopmentDiseaseDissectionEpithelial CellsExposure toExtrinsic asthmaFOXO1A geneFamilyFungal SporesGene ExpressionGeneticGoalsHumanITGAX geneIgEImmune responseIn VitroInflammatoryInhalationInterleukin-10Interleukin-13Knockout MiceLaboratoriesLungLung InflammationLymphocyteMediatingMethodsMicroRNAsMolecularMolecular AnalysisMolecular GeneticsMusMyeloid CellsPathogenesisPathologicPathway interactionsPatientsPattern recognition receptorPeptide HydrolasesProductionProteinase-Activated ReceptorsRefractoryRegulationRoleSeverity of illnessSuggestionTestingTherapeuticTransgenic MiceVeteransairway epitheliumairway hyperresponsivenessairway inflammationairway remodelingallergic airway diseaseallergic airway inflammationasthmaticasthmatic patientbasecell typecombatconditional knockoutcytokinefungusgenetic elementgenome-wideglobal healthimprovedin vivoinflammatory lung diseaseinsightmembermouse modelnovel diagnosticsnovel strategiesnovel therapeuticsprogramsresponsespecific biomarkersstandard caresuccesstooltranscriptome
项目摘要
The long-term objective of our laboratory is to understand the underlying molecular and genetic causes for
chronic allergic airway inflammation or asthma to improve therapeutic approaches. The specific objective of
this application is to dissect microRNA (miRNA)-dependent inflammatory pathways in dendritic cells (DCs) and
CD4+ T cells that modulate murine allergic airway disease to fungal allergens. Asthma is a major rising global
health threat that disproportionately affects combat veterans. We showed that patients with asthma often have
evidence of airway mycosis, defined as detection of fungi in airway secretions in association with specific
biomarkers (e.g. IgE or TH2 cells) reactive to one or more fungi. Our laboratory and others have shown that
fungal proteinases and fungal spores drive asthma-like airway disease in mice. Airway epithelial cells express
pattern recognition receptors (PRRs) for foreign antigens (e.g. TLRs, C-type lectin, and protease-activated
receptors) and important for conventional dendritic cell (cDC) activation and initiation of allergic CD4+ type 2
cell (TH2) and TH17 cell-dependent airway inflammation, IgE production, and airway hyperresponsiveness
(AHR), collectively termed allergic airway disease. We and others have shown the requirement of TH2 cells
and DC in the pathogenesis of allergic airway disease. We employed murine models of chronic allergic airway
inflammation, and detected aberrant expression of let-7 miRNA family in lung, CD4+ T cells and CD11c+ DCs.
Specifically, the expression of let-7b and let-7c (let-7bc-cluster) is reduced in sorted lung CD4+ T cells and
enhanced in CD11c+ antigen presenting cells (APCs) of mice with chronic allergic airway disease. Moreover,
mice that lack the let-7bc-cluster globally or specifically in CD4+ T cells or CD11c+ APCs show blunted TH2
responses and allergic disease. On the other hand enforced expression of let-7 specifically in CD4+ T cells
enhances fungus-induced allergic airway disease. The let-7b and let-7c members only account for only 9% of
total let-7 activity in lymphocytes and myeloid cells suggesting that let-7bc cluster critically determines gene
expression of CD4+ T cells and DCs that drive allergic sensitization to Aspergillus niger. Our central hypothesis
therefore states that the let-7 family modulates allergic airway disease severity and orchestrates activation of
cDCs and TH2 responses. We will address this hypothesis through the following Specific Aims: 1) Elucidate
the CD4+ T cell intrinsic requirement of the let-7bc-cluster in pathogenesis of allergic airway disease.
Hypothesis: The let-7bc-cluster regulates target gene expression in CD4+ T cells and controls TH2 lung
inflammation and allergic airway disease. 2) Determine the role of let-7bc-cluster in DC-mediated control of
allergic airway inflammation. Hypothesis: Induction of let-7bc-cluster expression in asthmatic lung cDCs directs
molecular programming of TH2 driven pulmonary allergic inflammation. Through these two aims, we will further
define the mechanisms by which the let-7bc cluster controls the expression of allergic airway disease,
providing novel diagnostic and therapeutic insight into asthma and related disorders.
我们实验室的长期目标是了解基本的分子和遗传原因
慢性过敏性气道炎症或哮喘以改善治疗方法。的具体目标
该应用是在树突状细胞(DC)和
调节鼠过敏性气道疾病对真菌过敏原的CD4+ T细胞。哮喘是全球的主要上升
健康威胁不成比例地影响战斗退伍军人。我们表明哮喘患者经常有
气道真菌病的证据,被定义为在气道分泌物中对真菌的检测
生物标志物(例如IgE或Th2细胞)对一个或多个真菌反应。我们的实验室和其他实验室表明
真菌蛋白酶和真菌孢子驱动小鼠哮喘样气道疾病。气道上皮细胞表达
外抗原的模式识别受体(PRR)(例如TLR,C型凝集素和蛋白酶激活
受体),对过敏CD4+ 2型的常规树突状细胞(CDC)激活和启动
细胞(TH2)和TH17细胞依赖性气道炎症,IgE产生和气道高反应性
(AHR),统称为过敏性气道疾病。我们和其他人表明了Th2细胞的要求
DC在过敏性气道疾病的发病机理中。我们采用了慢性过敏性气道的鼠模型
在肺,CD4+ T细胞和CD11C+ DC中,炎症并检测到Let-7 miRNA家族的异常表达。
具体而言,在排序的肺CD4+ T细胞和
患有慢性过敏性气道疾病的小鼠的CD11C+抗原呈递细胞(APC)增强。而且,
在全球或CD4+ T细胞或CD11C+ APC中缺少Let-7BC群集的小鼠显示出钝的Th2
反应和过敏性疾病。另一方面,在CD4+ T细胞中专门执行Let-7的表达
增强真菌引起的过敏性气道疾病。 Let-7B和Let-7C成员仅占9%
淋巴细胞和髓样细胞中的总let-7活性表明Let-7BC簇严重确定基因
CD4+ T细胞和DC的表达,这些CD4+ T细胞驱动过敏敏化尼日尔。我们的中心假设
因此,Let-7家族调节过敏性气道疾病严重程度,并策划激活
CDC和TH2响应。我们将通过以下特定目的解决这一假设:1)阐明
Let-7BC簇的CD4+ T细胞在过敏性气道疾病的发病机理中的固有需求。
假设:LET-7BC簇调节CD4+ T细胞中的靶基因表达并控制Th2肺
炎症和过敏性气道疾病。 2)确定Let-7BC群集在DC介导的对控制中的作用
过敏性气道炎症。假设:哮喘肺CDC中的Let-7BC簇表达的诱导
Th2驱动肺过敏性炎症的分子编程。通过这两个目标,我们将进一步
定义Let-7BC簇控制过敏性气道疾病表达的机制,
为哮喘和相关疾病提供新颖的诊断和治疗见解。
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 }}
DAVID B CORRY其他文献
DAVID B CORRY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('DAVID B CORRY', 18)}}的其他基金
Molecular and Cellular Dissection of miRNAs in Controlling Allergic Airway Inflammation in Mice
miRNA 在控制小鼠过敏性气道炎症中的分子和细胞解析
- 批准号:
10477187 - 财政年份:2020
- 资助金额:
-- - 项目类别:
Molecular and Cellular Dissection of miRNAs in Controlling Allergic Airway Inflammation in Mice
miRNA 在控制小鼠过敏性气道炎症中的分子和细胞解析
- 批准号:
10664926 - 财政年份:2020
- 资助金额:
-- - 项目类别:
MECHANISM AND FUNCTION OF LET-7, A NOVEL MODULATOR OF TH17-DEPENDENT EMPHYSEMA
TH17 依赖性肺气肿的新型调节剂 Let-7 的机制和功能
- 批准号:
10240489 - 财政年份:2018
- 资助金额:
-- - 项目类别:
MECHANISM AND FUNCTION OF LET-7, A NOVEL MODULATOR OF TH17-DEPENDENT EMPHYSEMA
TH17 依赖性肺气肿的新型调节剂 Let-7 的机制和功能
- 批准号:
10470262 - 财政年份:2018
- 资助金额:
-- - 项目类别:
Pathogenesis of Polymicrobial Cerebritis-Related Dementia
多种微生物脑炎相关痴呆的发病机制
- 批准号:
10119639 - 财政年份:2018
- 资助金额:
-- - 项目类别:
MECHANISM AND FUNCTION OF LET-7, A NOVEL MODULATOR OF TH17-DEPENDENT EMPHYSEMA
TH17 依赖性肺气肿的新型调节剂 Let-7 的机制和功能
- 批准号:
9766362 - 财政年份:2018
- 资助金额:
-- - 项目类别:
MECHANISM AND FUNCTION OF LET-7, A NOVEL MODULATOR OF TH17-DEPENDENT EMPHYSEMA
TH17 依赖性肺气肿的新型调节剂 Let-7 的机制和功能
- 批准号:
10001079 - 财政年份:2018
- 资助金额:
-- - 项目类别:
相似国自然基金
COPD气道黏液高分泌的CFTR调控机制及全真一气汤对其影响研究
- 批准号:81774103
- 批准年份:2017
- 资助金额:25.0 万元
- 项目类别:面上项目
受肺内微生物影响的NODAL分子在气道高反应性疾病中的作用及分子机制的研究
- 批准号:31670121
- 批准年份:2016
- 资助金额:62.0 万元
- 项目类别:面上项目
Notch信号通路影响气道平滑肌细胞合成基质金属蛋白酶12以促进COPD的机制探讨
- 批准号:81300031
- 批准年份:2013
- 资助金额:23.0 万元
- 项目类别:青年科学基金项目
NADPH氧化酶和线粒体UCP2蛋白影响人气道平滑肌细胞氧化/抗氧化平衡的作用及机制
- 批准号:81360004
- 批准年份:2013
- 资助金额:49.0 万元
- 项目类别:地区科学基金项目
慢性阻塞性肺疾病中DNA加合物对气道表遗传学和慢性炎症影响的研究
- 批准号:81070036
- 批准年份:2010
- 资助金额:32.0 万元
- 项目类别:面上项目
相似海外基金
Nuestro Sueno: Cultural Adaptation of a Couples Intervention to Improve PAP Adherence and Sleep Health Among Latino Couples with Implications for Alzheimer’s Disease Risk
Nuestro Sueno:夫妻干预措施的文化适应,以改善拉丁裔夫妇的 PAP 依从性和睡眠健康,对阿尔茨海默病风险产生影响
- 批准号:
10766947 - 财政年份:2023
- 资助金额:
-- - 项目类别:
The cardiovascular consequences of sleep apnea plus COPD (Overlap syndrome)
睡眠呼吸暂停加慢性阻塞性肺病(重叠综合征)对心血管的影响
- 批准号:
10733384 - 财政年份:2023
- 资助金额:
-- - 项目类别:
Gene regulatory networks in early lung epithelial cell fate decisions
早期肺上皮细胞命运决定中的基因调控网络
- 批准号:
10587615 - 财政年份:2023
- 资助金额:
-- - 项目类别:
A Low-Cost Wearable Connected Health Device for Monitoring Environmental Pollution Triggers of Asthma in Communities with Health Disparities
一种低成本可穿戴互联健康设备,用于监测健康差异社区中哮喘的环境污染诱因
- 批准号:
10601615 - 财政年份:2023
- 资助金额:
-- - 项目类别:
An Inhaled Microbiome-Targeted Biotherapeutic for Treatment of COPD
一种吸入性微生物组靶向生物治疗药物,用于治疗慢性阻塞性肺病
- 批准号:
10600887 - 财政年份:2023
- 资助金额:
-- - 项目类别: