Pulmonary Epithelial Dynamics and Innate Host Defense
肺上皮动力学和先天宿主防御
基本信息
- 批准号:10063952
- 负责人:
- 金额:$ 48.1万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2017
- 资助国家:美国
- 起止时间:2017-12-07 至 2022-11-30
- 项目状态:已结题
- 来源:
- 关键词:Adrenal Cortex HormonesAffectAir SacsAlveolarAlveolitisAlveolusApoptosisApoptoticBRAF geneBindingBronchiolitisBronchitisCell CycleCell ProliferationCell modelCell surfaceCellsCenters for Disease Control and Prevention (U.S.)Cessation of lifeChronicClinicalCough HeadachesCoughingCytoplasmDataDevelopmentDoseElderlyEndocytosisEpidemicEpithelialEpithelial CellsEventFRAP1 geneFeverFibroblast Growth Factor ReceptorsGenesGenetic ModelsGoalsHost DefenseHumanHyperoxiaImmuneIn VitroIncidenceInfectionInfluenzaInfluenza A Virus, H1N1 SubtypeInfluenza A virusInhalationIntegration Host FactorsLigand BindingLungMAP Kinase GeneMAPK Signaling Pathway PathwayMEKsMembrane GlycoproteinsMitogensModelingMouse Cell LineMusMyalgiaNatural ResistancePI3K/AKTPathway interactionsPlayPneumoniaPre-Clinical ModelPredispositionProcessProductionProphylactic treatmentProteinsPulmonary Heart DiseaseRNA VirusesRandomized Controlled TrialsReceptor Protein-Tyrosine KinasesRecoveryResistanceResistance to infectionRoleSeveritiesSialic AcidsSignal TransductionSirolimusStimulusSyndromeTamoxifenTestingTherapeuticTracheitisTubeViralVirusVirus DiseasesVirus Replicationalveolar epitheliumalveolar type II cellin vivoinfluenza infectioninfluenza pneumoniainfluenzavirusinhibitor/antagonistkeratinocyte growth factorlung injurymTOR Inhibitormortalitynovelnovel strategiesprenatal cigarette smokingresistance mechanismsialic acid receptor
项目摘要
Project Summary
The RNA virus that causes influenza is inhaled into the airways and binds to terminal sialic acid residues on
host cell surface glycoproteins via viral sialic acid receptors. The tracheitis, bronchitis and bronchiolitis that
results is often accompanied by incapacitating cough, headache, fever and myalgias, but the syndrome usually
resolves in 7-10 days without development of alveolitis. This is fortunate because once the pulmonary
parenchyma is involved, mortality increases almost 60 fold, from 0.3 to 17.8 annual deaths per 100,000(2006
CDC data). Because we believe that infection of alveolar type II (ATII) cells is the pivotal event in the
conversion of a self-limited influenza virus (IV) airway infection to a potentially lethal alveolar infection, our
proposal focuses on the mechanisms that render the ATII cells resistant or susceptible to infection with IV.
Although ATII cells are clearly the primary epithelial target for IV in the alveolus, they are remarkably resistant
to IV infection in their typically quiescent state in the unperturbed lung, in which fewer than 1% of ATII cells are
cycling. Recent in vitro studies have demonstrated that the PI3K/Akt/mTOR pathway, which regulates cellular
proliferation, plays a key role in susceptibility and severity of IV infection by enhancing cell surface binding,
endocytosis, lysosomal acidification driven entry into the cytoplasm, replication using cellular translational
machinery, and anti-apoptotic mechanisms that prolong viral production. Mitogenic stimulation of
PI3K/Akt/mTOR pathway with intrapulmonary keratinocyte growth factor (KGF) converts ATII cells from a
quiescent, IV resistant state to a proliferative, IV susceptible state, and hastens the progression of IV infection
from the conducting airways to the alveolus, markedly accelerating mortality. Our hypothesis is that key host
factors, such as transient hyperoxia, render hosts susceptible to influenza pneumonia (IP) through their impact
on the proliferative tone of the ATII pool. Our goals are to determine the mechanisms of mitogen-induced
susceptibility to influenza A virus susceptibility by completing three specific aims: 1) mechanisms of mitogen-
induced susceptibility of AECII cells to IAV infection, 2) host states that affect IAV susceptibility through
mitogenic effects on AECII cells, 3) genetic models of AECII signaling and anti-proliferative strategies for IAV
prophylaxis and therapy. Successful completion of these aims will reveal the importance of a paradigm-shifting,
AECII-centric host susceptibility mechanism, and suggest novel approaches to influenza prophylaxis and
therapy.
项目概要
引起流感的RNA病毒被吸入呼吸道并与呼吸道末端唾液酸残基结合。
通过病毒唾液酸受体作用于宿主细胞表面糖蛋白。气管炎、支气管炎和细支气管炎
结果常常伴有咳嗽、头痛、发烧和肌痛,但该综合征通常
7-10 天内消退,不会出现肺泡炎。这是幸运的,因为一旦肺部
涉及实质组织,死亡率增加近 60 倍,从每年每 10 万人死亡 0.3 人增加到 17.8 人(2006 年)
疾病预防控制中心数据)。因为我们相信 II 型肺泡 (ATII) 细胞的感染是整个过程的关键事件。
自限性流感病毒(IV)气道感染转化为潜在致命的肺泡感染,我们的
该提案的重点是使 ATII 细胞对 IV 感染具有抵抗力或易感性的机制。
尽管 ATII 细胞显然是肺泡内 IV 的主要上皮靶标,但它们具有显着的耐药性
在未受干扰的肺部中,IV 感染处于典型的静止状态,其中只有不到 1% 的 ATII 细胞
骑自行车。最近的体外研究表明,PI3K/Akt/mTOR 通路可调节细胞
增殖,通过增强细胞表面结合,在 IV 感染的易感性和严重程度中发挥关键作用,
内吞作用,溶酶体酸化驱动进入细胞质,使用细胞翻译复制
延长病毒生产的机械和抗凋亡机制。有丝分裂刺激
PI3K/Akt/mTOR 通路与肺内角质形成细胞生长因子 (KGF) 将 ATII 细胞从
静态、IV 抵抗状态转变为增殖、IV 易感状态,并加速 IV 感染的进展
从传导气道到肺泡,显着加速死亡率。我们的假设是关键宿主
暂时性高氧等因素通过其影响使宿主易患流感肺炎 (IP)
ATII池的增殖基调。我们的目标是确定丝裂原诱导的机制
通过完成三个具体目标来评估对甲型流感病毒的易感性:1)丝裂原的机制
诱导 AECII 细胞对 IAV 感染的易感性,2) 宿主状态通过影响 IAV 易感性
对 AECII 细胞的促有丝分裂作用,3) AECII 信号传导的遗传模型和 IAV 的抗增殖策略
预防和治疗。成功完成这些目标将揭示范式转变的重要性,
以 AECII 为中心的宿主易感性机制,并提出流感预防和治疗的新方法
治疗。
项目成果
期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Viral Evasion of Innate Immune Defense: The Case of Resistance of Pandemic H1N1 Influenza A Virus to Human Mannose-Binding Proteins.
- DOI:10.3389/fmicb.2021.774711
- 发表时间:2021
- 期刊:
- 影响因子:5.2
- 作者:White MR;Nikolaidis NM;McCormack F;Crouch EC;Hartshorn KL
- 通讯作者:Hartshorn KL
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Francis Xavier McCormack其他文献
Francis Xavier McCormack的其他文献
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{{ truncateString('Francis Xavier McCormack', 18)}}的其他基金
Role of Pulmonary Osteoclast-Like Cells in Lung Injury
肺破骨细胞样细胞在肺损伤中的作用
- 批准号:
10395922 - 财政年份:2021
- 资助金额:
$ 48.1万 - 项目类别:
Role of Pulmonary Osteoclast-Like Cells in Lung Injury
肺破骨细胞样细胞在肺损伤中的作用
- 批准号:
10115416 - 财政年份:2021
- 资助金额:
$ 48.1万 - 项目类别:
Role of Pulmonary Osteoclast-Like Cells in Lung Injury
肺破骨细胞样细胞在肺损伤中的作用
- 批准号:
10620655 - 财政年份:2021
- 资助金额:
$ 48.1万 - 项目类别:
Multicenter Interventional Lymphangioleiomyomatosis Early Disease Trial (MILED)-CCC
多中心介入性淋巴管平滑肌瘤病早期疾病试验(MILED)-CCC
- 批准号:
10219338 - 财政年份:2016
- 资助金额:
$ 48.1万 - 项目类别:
Multicenter Interventional Lymphangioleiomyomatosis Early Disease Trial (MILED)-CCC
多中心介入性淋巴管平滑肌瘤病早期疾病试验(MILED)-CCC
- 批准号:
9742512 - 财政年份:2016
- 资助金额:
$ 48.1万 - 项目类别:
Multicenter Interventional Lymphangioleiomyomatosis Early Disease Trial (MILED)-CCC
多中心介入性淋巴管平滑肌瘤病早期疾病试验(MILED)-CCC
- 批准号:
9355218 - 财政年份:2016
- 资助金额:
$ 48.1万 - 项目类别:
Multicenter Interventional Lymphangioleiomyomatosis Early Disease Trial (MILED)-CCC
多中心介入性淋巴管平滑肌瘤病早期疾病试验(MILED)-CCC
- 批准号:
9520409 - 财政年份:2016
- 资助金额:
$ 48.1万 - 项目类别:
Pathogenesis-Driven Therapeutic Development for Pulmonary Alveolar Microlithiasis
肺泡微石症的发病机制驱动的治疗开发
- 批准号:
9247827 - 财政年份:2015
- 资助金额:
$ 48.1万 - 项目类别:
Pathogenesis-Driven Therapeutic Development for Pulmonary Alveolar Microlithiasis
肺泡微石症的发病机制驱动的治疗开发
- 批准号:
9032527 - 财政年份:2015
- 资助金额:
$ 48.1万 - 项目类别:
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