Loss of Endothelial S1PR1 Drives Post-Influenza Pulmonary Fibrosis
内皮 S1PR1 的缺失导致流感后肺纤维化
基本信息
- 批准号:10634045
- 负责人:
- 金额:$ 73.98万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-06-15 至 2028-05-31
- 项目状态:未结题
- 来源:
- 关键词:2019-nCoVAcute Respiratory Distress SyndromeAffectAlveolarArchitectureAttenuatedAutomobile DrivingBackBleomycinBlood VesselsBronchoalveolar Lavage FluidCOVID-19COVID-19 pandemicCell CommunicationCell surfaceCellsChronicClinical TrialsCoculture TechniquesCollagenComplicationContractsCoronavirusCoughingCoupledDepositionDevelopmentDown-RegulationEffector CellEndothelial CellsEndotheliumExtracellular MatrixFibroblastsFibrosisFunctional disorderGene Expression ProfileGeneticGenetic TranscriptionHumanInfluenzaInfluenza A virusInjuryInterleukin-1 alphaInterruptionInterventionLeadLungMechanical ventilationMediatingMediatorMessenger RNAModelingMolecularMusOutcomePathologicPhasePhosphorylationPhysiologicalPlayProcessProductionPulmonary FibrosisRecombinantsRecyclingRespiration DisordersRespiratory FailureRoleSeveritiesShortness of BreathSignal InductionSignal TransductionSphingosine-1-Phosphate ReceptorSterilitySurfaceSurvivorsSystemTestingTherapeuticTissuesTransgenic MiceVascular PermeabilitiesViralViral Respiratory Tract InfectionVirus Diseasesclinically relevantdisabilitydisabling symptomefficacy validationendothelial dysfunctionepidemic virusexercise intolerancegain of functionin vivoinfluenzavirusloss of functionlung injurylung repairmortalitymouse modelnew therapeutic targetnovelnovel strategiesnovel therapeutic interventionnovel therapeuticsoverexpressionpharmacologicpreventprotein expressionreceptorrepairedresponsesphingosine 1-phosphatetissue repairtranscriptomics
项目摘要
Project Summary
Respiratory viral infections such as influenza and coronaviruses are frequent causes of acute respiratory distress
syndrome (ARDS), a disabling condition with a mortality up to 46%. While supportive interventions have reduced
the overall mortality of ARDS, severe cases requiring prolonged mechanical ventilation remain common, and
many cases are complicated by the development of fibrosis in the lung. Post-viral pulmonary fibrosis can lead to
chronic disability due to respiratory dysfunction, exercise intolerance and disabling symptoms such as shortness
of breath and cough. Endothelial injury and dysfunction contribute to the severity of ARDS, persistence of lung
injury, and dysregulated tissue repair. Currently there are no therapies to prevent the development of post-viral
pulmonary fibrosis, and in fact supportive mechanical ventilation may further perpetuate pathological endothelial
injury and worsen fibrotic outcomes.
The sphingosine-1-phosphate (S1P)-S1P receptor 1 (S1PR1) signaling axis on endothelial cells (EC) is a key
modulator of endothelial function, including a regulatory role in vascular permeability. However, the role of
S1PR1 during the fibroproliferative phase of pulmonary viral infection induced ARDS has not been well explored.
Specifically, cross talk between EC and lung fibroblasts, key effector cells in the development of pulmonary
fibrosis because of their production of extracellular matrix and their ability to contract and distort tissue
architecture, has not been defined. Reversing endothelial dysfunction and restoring pulmonary vascular integrity
via augmentation of EC S1PR1 after viral infection could have great therapeutic value by preventing the
development of post-viral pulmonary fibrosis.
Our preliminary results demonstrate that persistent loss of endothelial S1PR1 is deleterious during influenza A
virus (IAV) infection, resulting in increased vascular permeability and increased pulmonary fibrosis. We
hypothesize that IAV infection induced lung injury induces loss of EC S1PR1, leading to altered EC-fibroblast
cross talk which drives fibrosis. Furthermore, we propose that augmenting EC S1PR1 expression in the context
of IAV infection will lead to the development of a novel anti-fibrotic strategy. We will use endothelial specific gain-
of-function and loss-of-function mice in an IAV infection model to determine how IAV infection drives sustained
reduction of EC S1PR1 (Aim 1), how EC S1PR1 affects transcriptomic signatures and cross talk with fibroblasts
after IAV infection (Aim 2), and how augmentation of EC S1PR1 can be used in a therapeutic manner to prevent
post-IAV pulmonary fibrosis (Aim 3). A better understanding of the molecular mechanisms and sequelae of EC
dysfunction after IAV and the effects on subsequent fibroproliferation will lead to novel therapeutics to prevent
this debilitating complication of pulmonary viral infections.
项目摘要
呼吸道病毒感染如流感和冠状病毒是急性呼吸窘迫的常见原因
急性呼吸窘迫综合征(ARDS)是一种致残性疾病,死亡率高达46%。虽然支持性干预措施减少了
ARDS的总死亡率,需要长时间机械通气的严重病例仍然很常见,
许多病例由于肺纤维化的发展而变得复杂。病毒感染后肺纤维化可导致
由于呼吸功能障碍、运动不耐受和短粗等致残症状导致的慢性残疾
呼吸和咳嗽。内皮细胞损伤和功能障碍与ARDS的严重程度、肺功能的持续存在有关,
损伤和失调的组织修复。目前还没有治疗方法来预防病毒感染后的发展。
肺纤维化,事实上,支持性机械通气可能进一步使病理性内皮细胞
损伤和恶化纤维化结果。
内皮细胞(EC)上的鞘氨醇-1-磷酸(S1 P)-S1 P受体1(S1 PR 1)信号传导轴是一个关键,
内皮功能的调节剂,包括在血管通透性中的调节作用。但是,作用
S1 PR 1在肺病毒感染诱导的ARDS的纤维增生期尚未得到很好的探索。
具体而言,EC和肺成纤维细胞之间的串扰,肺成纤维细胞是肺成纤维细胞发展中的关键效应细胞。
由于它们产生细胞外基质以及它们收缩和扭曲组织的能力,
架构尚未定义。逆转内皮功能障碍和恢复肺血管完整性
通过增强病毒感染后的EC S1 PR 1,
病毒感染后肺纤维化的发展。
我们的初步结果表明,在甲型流感期间,内皮S1 PR 1的持续缺失是有害的。
病毒(IAV)感染,导致血管通透性增加和肺纤维化增加。我们
假设IAV感染诱导的肺损伤诱导EC S1 PR 1丢失,导致改变的EC成纤维细胞
导致纤维化的串扰此外,我们提出,在这种情况下,增加EC S1 PR 1表达,
IAV感染将导致一种新的抗纤维化策略的发展。我们将使用内皮细胞特异性增益-
在IAV感染模型中的功能丧失和功能丧失小鼠,以确定IAV感染如何驱动持续的
EC S1 PR 1的减少(目的1),EC S1 PR 1如何影响转录组特征和与成纤维细胞的串扰
IAV感染后(目的2),以及如何以治疗方式使用EC S1 PR 1增强,以预防
IAV后肺纤维化(目的3)。更好地了解EC的分子机制和后遗症
IAV后的功能障碍和对随后的纤维增生的影响将导致新的治疗方法,以防止
肺部病毒感染的并发症
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 }}
Rachel S Knipe其他文献
Rachel S Knipe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('Rachel S Knipe', 18)}}的其他基金
Histologic and Transcriptional Profiling of Endothelial Cells During Progressive Pulmonary Fibrosis
进行性肺纤维化期间内皮细胞的组织学和转录谱
- 批准号:
10616601 - 财政年份:2022
- 资助金额:
$ 73.98万 - 项目类别:
Histologic and Transcriptional Profiling of Endothelial Cells During Progressive Pulmonary Fibrosis
进行性肺纤维化期间内皮细胞的组织学和转录谱
- 批准号:
10419046 - 财政年份:2022
- 资助金额:
$ 73.98万 - 项目类别:
Role and regulation of vascular permeability in pulmonary fibrosis
血管通透性在肺纤维化中的作用和调节
- 批准号:
9756465 - 财政年份:2018
- 资助金额:
$ 73.98万 - 项目类别:
Role and regulation of vascular permeability in pulmonary fibrosis
血管通透性在肺纤维化中的作用和调节
- 批准号:
10223415 - 财政年份:2018
- 资助金额:
$ 73.98万 - 项目类别:
Role and regulation of vascular permeability in pulmonary fibrosis
血管通透性在肺纤维化中的作用和调节
- 批准号:
10457937 - 财政年份:2018
- 资助金额:
$ 73.98万 - 项目类别:
相似海外基金
Combining Mechanistic Modelling with Machine Learning for Diagnosis of Acute Respiratory Distress Syndrome
机械建模与机器学习相结合诊断急性呼吸窘迫综合征
- 批准号:
EP/Y003527/1 - 财政年份:2024
- 资助金额:
$ 73.98万 - 项目类别:
Research Grant
The Association Between Aging, Inflammation, and Clinical Outcomes in Acute Respiratory Distress Syndrome
衰老、炎症与急性呼吸窘迫综合征临床结果之间的关联
- 批准号:
10722669 - 财政年份:2023
- 资助金额:
$ 73.98万 - 项目类别:
Sedatives Pharmacology in Acute Respiratory Distress Syndrome- SPA
急性呼吸窘迫综合征中的镇静药理学 - SPA
- 批准号:
491387 - 财政年份:2023
- 资助金额:
$ 73.98万 - 项目类别:
Fellowship Programs
New mechanism-based TREM-1 therapy for acute respiratory distress syndrome
基于新机制的 TREM-1 疗法治疗急性呼吸窘迫综合征
- 批准号:
10678788 - 财政年份:2023
- 资助金额:
$ 73.98万 - 项目类别:
Great Lakes Clinical Center of the Acute Respiratory Distress Syndrome, Pneumonia and Sepsis (APS) Consortium
急性呼吸窘迫综合征、肺炎和败血症 (APS) 联盟五大湖临床中心
- 批准号:
10646578 - 财政年份:2023
- 资助金额:
$ 73.98万 - 项目类别:
Effect of ADAMTS13 on pathogenesis of acute respiratory distress syndrome
ADAMTS13 对急性呼吸窘迫综合征发病机制的影响
- 批准号:
23K08447 - 财政年份:2023
- 资助金额:
$ 73.98万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
A Novel Synthetic Biology-Derived Microbiome Therapeutic to Treat Viral-Induced Acute Respiratory Distress Syndrome (ARDS)
一种新型合成生物学衍生的微生物疗法,可治疗病毒引起的急性呼吸窘迫综合征(ARDS)
- 批准号:
10601865 - 财政年份:2023
- 资助金额:
$ 73.98万 - 项目类别:
Development of drug therapy targeting ferroptosis, iron-dependent cell death for acute respiratory distress syndrome.
开发针对铁死亡(急性呼吸窘迫综合征的铁依赖性细胞死亡)的药物疗法。
- 批准号:
23K08360 - 财政年份:2023
- 资助金额:
$ 73.98万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Sustainable Implementation of Prone Positioning for the Acute Respiratory Distress Syndrome
持续实施俯卧位治疗急性呼吸窘迫综合征
- 批准号:
10722194 - 财政年份:2023
- 资助金额:
$ 73.98万 - 项目类别:
Point-of-care system to assess the risk of trauma-induced acute respiratory distress syndrome
用于评估创伤引起的急性呼吸窘迫综合征风险的护理点系统
- 批准号:
10594793 - 财政年份:2023
- 资助金额:
$ 73.98万 - 项目类别: