Mechanistic Insights of TIMP-1 in Influenza Virus Infection
TIMP-1 在流感病毒感染中的机制见解
基本信息
- 批准号:10615782
- 负责人:
- 金额:$ 7.55万
- 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:2022-05-01 至 2025-04-30
- 项目状态:未结题
- 来源:
- 关键词:18 year oldActivated LymphocyteAcute Lung InjuryAntiviral AgentsApoptoticAttenuatedB-Cell ActivationB-LymphocytesBacterial PneumoniaBiological Response ModifiersBlood VesselsBlood capillariesBody Weight decreasedCapillary PermeabilityCell ProliferationCellsCessation of lifeDataDevelopmentDiagnosisExtracellular MatrixExtracellular Matrix DegradationFutureGoalsHealthcareHospitalizationImmune responseImmunofluorescence ImmunologicImpairmentIn VitroIndividualInflammatory ResponseInfluenzaInfluenza A Virus, H1N1 SubtypeInfluenza A virusInvestigational DrugsKnowledgeLinkLungMatrix Metalloproteinase InhibitorMatrix MetalloproteinasesMeasuresMediatingMorbidity - disease rateMultiple Organ FailureMusMyofibroblastOseltamivirOutcomeOxygenPathogenesisPatientsPeptide HydrolasesPlasmaProteinsPulmonary InflammationRegulationRoleSeasonsSeveritiesStainsStructure of parenchyma of lungT-LymphocyteTestingTissue Inhibitor of Metalloproteinase-1VaccinatedVaccineeVaccinesViral ProteinsVirusVirus DiseasesVirus ReplicationWild Type Mouseadaptive immune responsecare burdencell typecytokine release syndromeeffective therapyepidemic virusexperimental studyfluglobal healthhuman subjectinfluenza infectioninsightlung injurymortalitynew therapeutic targetnovelpandemic diseasepreventprotective effectrecruitsafety testingseasonal influenzatherapeutic targettransdifferentiationvaccine development
项目摘要
PROJECT SUMMARY/ ABSTRACT
Influenza A virus (IAV) epidemics are associated with high morbidity and mortality. Complications such as the
development of secondary bacterial pneumonia and cytokine storm leading to multi-organ failure increase
morbidity and mortality. Although vaccines are developed annually for emerging IAV strains, not all subjects
are vaccinated or able to mount robust protective immune responses to the vaccines. Anti-viral drugs such as
oseltamivir are not fully effective at preventing mortality associated with severe IAV infections. Thus, there is
an urgent need to identify new therapeutic targets to facilitate the development of more effective antiviral
agents to limit the high global healthcare burden associated with IAV infections. TIMP-1 (tissue inhibitor of
metalloproteinases 1) controls the enzymatic activity of matrix metalloproteinases (MMPs) and is well-known
for regulating extracellular matrix (ECM) turnover, but its contributions to the pathogenesis of IAV disease have
not been deeply explored. Our novel preliminary data showed that plasma TIMP-1 levels are significantly
upregulated in patients diagnosed with pandemic H1N1 and seasonal IAV infections, and levels correlate
inversely with the PaO2/FiO2 ratio. Furthermore, our data using immunofluorescence staining suggested TIMP-
1 is dramatically induced in lipofibroblasts. Compared with WT mice, Timp-1-/- mice have reduced H1N1 IAV-
induced body weight loss; mortality; lung injury; increased adaptive immune responses and T cell and B cell
activation, and attenuated capillary leak. Based on our data, TIMP-1 might serve as a novel therapeutic target
during serious IAV infection. The experiments proposed in this application aim to 1) identify the regulation and
function of TIMP-1 during the IAV infection; 2) provide novel insights into the mechanism by which Timp-1
deficiency provides better outcomes during IAV infection. Successful completion of these studies will pave the
way for future investigational new drug (IND)-enabling studies to test the safety and efficacy of a “first in class”
therapeutic targeting the host response to reduce the morbidity and mortality associated with serious IAV
infection.
项目总结/摘要
甲型流感病毒(IAV)流行与高发病率和死亡率相关。等并发症
继发性细菌性肺炎和细胞因子风暴的发展导致多器官衰竭增加
发病率和死亡率。尽管每年都有针对新出现的IAV毒株的疫苗开发,但并非所有受试者都能获得疫苗。
接种疫苗或能够对疫苗产生强有力的保护性免疫应答。抗病毒药物,如
奥司他韦在预防与严重IAV感染相关的死亡率方面并不完全有效。因此,
迫切需要确定新的治疗靶点,以促进更有效的抗病毒药物的开发,
药物,以限制与IAV感染相关的高全球医疗负担。TIMP-1(TIMP-1组织抑制剂)
金属蛋白酶1)控制基质金属蛋白酶(MMP)的酶活性,并且是众所周知的
调节细胞外基质(ECM)周转,但其对IAV疾病发病机制的贡献,
没有被深入探索。我们的新的初步数据表明,血浆TIMP-1水平显著高于正常对照组。
在诊断为大流行性H1N1和季节性IAV感染的患者中上调,并且水平与
与PaO 2/FiO 2比值成反比。此外,我们使用免疫荧光染色的数据表明,TIMP-
1在脂肪成纤维细胞中显著诱导。与WT小鼠相比,Timp-1-/-小鼠具有减少的H1N1 IAV-
诱导的体重减轻;死亡率;肺损伤;适应性免疫应答和T细胞和B细胞增加
激活和减弱的毛细渗漏。基于我们的数据,TIMP-1可能作为一个新的治疗靶点
严重的IAV感染。本申请中提出的实验旨在1)识别调节,
TIMP-1在IAV感染过程中的功能; 2)为TIMP-1在IAV感染过程中的作用机制提供了新的见解。
缺乏在IAV感染期间提供更好的结果。这些研究的成功完成将为
未来研究性新药(IND)的方式-使研究能够测试“同类第一”的安全性和有效性
治疗靶向宿主反应,以降低与严重IAV相关的发病率和死亡率
感染
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)
Long Noncoding RNA: A Novel Insight into the Pathogenesis of Acute Lung Injury.
- DOI:10.3390/jcm12020604
- 发表时间:2023-01-11
- 期刊:
- 影响因子:3.9
- 作者:
- 通讯作者:
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Xiaoyun Wang其他文献
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{{ truncateString('Xiaoyun Wang', 18)}}的其他基金
Mechanistic Insights of TIMP-1 in Influenza Virus Infection
TIMP-1 在流感病毒感染中的机制见解
- 批准号:
10431082 - 财政年份:2022
- 资助金额:
$ 7.55万 - 项目类别:
MMP-8 Deficiency Improves Host Responses to Influenza Viral Infections
MMP-8 缺乏可改善宿主对流感病毒感染的反应
- 批准号:
9760647 - 财政年份:2019
- 资助金额:
$ 7.55万 - 项目类别:
MMP-8 Deficiency Improves Host Responses to Influenza Viral Infections
MMP-8 缺乏可改善宿主对流感病毒感染的反应
- 批准号:
10264958 - 财政年份:2019
- 资助金额:
$ 7.55万 - 项目类别:
MMP-8 Deficiency Improves Host Responses to Influenza Viral Infections
MMP-8 缺乏可改善宿主对流感病毒感染的反应
- 批准号:
10260933 - 财政年份:2019
- 资助金额:
$ 7.55万 - 项目类别:














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