Understanding Dysregulated Crosstalk Between Regulatory T Cells and Lung Dendritic Cells in the Pathogenesis of Chronic Obstructive Pulmonary Disease
了解慢性阻塞性肺疾病发病机制中调节性 T 细胞和肺树突状细胞之间的失调串扰
基本信息
- 批准号:10746742
- 负责人:
- 金额:$ 4.01万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-05-16 至 2025-07-15
- 项目状态:未结题
- 来源:
- 关键词:AccelerationAdoptive TransferAirAutomobile DrivingBlocking AntibodiesBreathingCause of DeathCell SeparationCell TherapyCell physiologyCellsChronic Obstructive Pulmonary DiseaseClinicalClinical TrialsCoculture TechniquesComplementConsentCoughingCytokine SignalingDataDendritic CellsDevelopmentDiseaseDisease ProgressionDisease modelEnvironmentEpithelial CellsEquipmentExcisionFeedbackFlow CytometryGenesGoalsHealthcare SystemsHomeostasisHost DefenseHumanImmuneImmune systemImmunologyImmunosuppressionImmunotherapyIndividualInfiltrationInflammatoryInhalationKnowledgeLaboratoriesLeukocytesLocationLungLung diseasesMeasuresMichiganMicroscopyModelingMorbidity - disease rateMucous body substanceMusNatural Killer CellsOperative Surgical ProceduresOxidantsPathogenesisPatientsPhenotypePopulationProductionProgressive DiseasePulmonary EmphysemaRegulationRegulatory T-LymphocyteResearchRoleSamplingSmokeSmokerStructure of parenchyma of lungT cell differentiationT-Cell ProliferationT-LymphocyteT-Lymphocyte SubsetsTestingTherapeuticTrainingTranslational ResearchUnited StatesUniversity resourcesairway obstructioncell killingcigarette smokecigarette smoke-induced COPDcytokinecytotoxicityeffector T cellexposure to cigarette smokehuman datainflammatory milieumembermicroscopic imagingmortalitymouse modelnovel therapeutic interventionpolarized cellpre-clinicalpreventprogramspulmonary functionpulmonary function declineresponsetherapy developmenttime use
项目摘要
Chronic obstructive pulmonary disease (COPD) is a highly prevalent lung disease and is the 4th leading cause
of death in the world. COPD results from inhalation of oxidants, such as cigarette smoke, which causes
inflammatory cell infiltration and lung destruction. COPD is a progressive disease leading to significant
morbidity and mortality. There are no therapies to halt the decline in lung function. Our long-term goal is to
understand the mechanisms underlying COPD pathogenesis so that we can develop an immunotherapy to
stop disease progression. T regulatory cells (Tregs) decreased in the lungs of smokers with COPD compared
to smokers without COPD. Lung dendritic cells (DCs), which are able to polarize T cells to become Tregs or T
effector cells (Teff), are more mature in COPD, suggesting that they have a pro-inflammatory as opposed to a
tolerogenic phenotype. We hypothesize that in COPD, the increased number of mature pro-inflammatory DCs
are driving T cells towards Teff phenotype, whereas under normal conditions, tolerogenic DCs would be more
likely to promote induction of Tregs. In return, Tregs can modulate DC phenotype and function, suggesting
that subtle crosstalk feedback mechanisms are involved in the regulation of DC and Treg. However, no studies
have looked at whether dysregulated crosstalk between Treg and DC populations contributes to COPD
pathogenesis. Our specific aims are: 1) to demonstrate that COPD is associated with a shift from tolerogenic to
pro-inflammatory DCs; 2) to show that pro-inflammatory DCs preferentially polarize T cells towards a Teff
phenotype compared to tolerogenic DCs; and 3) to provide evidence that the transfer of Tregs will restore the
number of tolerogenic DCs in the lung. This proposal will utilize an established murine cigarette-smoke based
COPD model and also excess human lung tissue from consented patients undergoing clinically-indicated lung
surgeries, both with and without COPD. This allows us to conduct translational research and take
observations from human samples to the mouse model where we can answer more mechanistic questions.
Despite the abundance of clinical trials related to Treg therapy, there are currently no similar trials looking at
Tregs in patients with COPD. Successful completion of this proposal will fill critical gaps in knowledge and
provide pre-clinical data in support of exploring Treg therapy for COPD patients. This proposal will take place
with the combined resources of the University of Michigan and the VA Ann Arbor Healthcare System (the
physical location of the laboratory). There are world-class facilities at both locations. The VA houses a murine
smoke-exposure facility, Microscopy Core, and FACSAria sorter, and all equipment and space needed to
conduct the research. Many members of the Immunology Graduate Program have labs at the VA, making for
a robust scientific environment. The training plan developed to successfully complete this proposal includes
advanced training in acquisition and analysis of fluorescent microscopy images, laboratory-specific training for
the study of lung leukocytes, and training in human research protections and the analysis of human data.
慢性阻塞性肺疾病(COPD)是一种高度流行的肺部疾病,是第四大病因
世界上的死亡。慢性阻塞性肺病是由于吸入氧化剂,如香烟烟雾,
炎性细胞浸润和肺破坏。慢性阻塞性肺病是一种进行性疾病,会导致严重的
发病率和死亡率。没有治疗方法可以阻止肺功能的下降。我们的长期目标是
了解COPD发病机制,以便我们能够开发免疫疗法,
阻止疾病发展。COPD吸烟者肺内调节性T细胞(TcR)减少,
没有COPD的吸烟者肺树突状细胞(DC),能够使T细胞活化成为T细胞或T淋巴细胞。
效应细胞(Teff)在COPD中更成熟,这表明它们具有促炎作用,而不是促炎作用。
致耐受表型我们假设在COPD中,成熟的促炎性DC数量的增加,
是驱动T细胞向Teff表型,而在正常条件下,致耐受性DC将更多
可能会促进THP的诱导。反过来,TdR可以调节DC的表型和功能,表明
微妙的串扰反馈机制参与了DC和Treg的调节。然而,没有研究
研究了Treg和DC群体之间失调的串扰是否会导致COPD
发病机制我们的具体目标是:1)证明COPD与从致耐受性转变为
促炎DC; 2)显示促炎DC优先将T细胞朝向Teff
表型;和3)提供证据表明TcB的转移将恢复TcB的表型。
肺中致耐受性DC的数量。该提案将利用一个建立的基于鼠烟雾的
COPD模型以及来自接受临床指征肺移植的知情同意患者的过量人肺组织
手术,无论是否患有COPD。这使我们能够进行转化研究,
从人类样本到小鼠模型的观察,我们可以回答更多的机械问题。
尽管有大量与Treg治疗相关的临床试验,但目前还没有类似的试验,
COPD患者中的甲状腺激素。成功完成本建议书将填补知识方面的关键空白,
为探索COPD患者的Treg治疗提供临床前数据。这项提议将在
与密歇根大学和弗吉尼亚州安阿伯医疗保健系统(
实验室的物理位置)。这两个地方都有世界一流的设施。退伍军人事务部养了一只老鼠
烟雾暴露设施、显微镜核心和FACSAria分选机,以及
进行研究。免疫学研究生项目的许多成员在VA拥有实验室,
强大的科学环境。为成功完成本建议书而制定的培训计划包括
荧光显微镜图像采集和分析的高级培训,
肺白细胞的研究,以及人体研究保护和人体数据分析方面的培训。
项目成果
期刊论文数量(0)
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Dawit Mengistu其他文献
Dawit Mengistu的其他文献
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{{ truncateString('Dawit Mengistu', 18)}}的其他基金
Understanding Dysregulated Crosstalk Between Regulatory T Cells and Lung Dendritic Cells in the Pathogenesis of Chronic Obstructive Pulmonary Disease
了解慢性阻塞性肺疾病发病机制中调节性 T 细胞和肺树突状细胞之间的失调串扰
- 批准号:
10460830 - 财政年份:2022
- 资助金额:
$ 4.01万 - 项目类别:
MetaboQuest: A Suite of Tools for Metabolite Annotation
MetaboQuest:代谢物注释工具套件
- 批准号:
10570907 - 财政年份:2022
- 资助金额:
$ 4.01万 - 项目类别:
MetaboQuest: A Suite of Tools for Metabolite Annotation
MetaboQuest:代谢物注释工具套件
- 批准号:
10395223 - 财政年份:2022
- 资助金额:
$ 4.01万 - 项目类别:
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