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

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.
项目摘要/摘要 甲型流感病毒(IAV)流行与高发病率和高死亡率有关。并发症,如 继发性细菌性肺炎和细胞因子风暴导致多器官衰竭增加 发病率和死亡率。尽管针对新出现的IAV毒株每年都会开发疫苗,但并非所有受试者 接种疫苗或能够对疫苗产生强大的保护性免疫反应。抗病毒药物,如 奥司他韦在预防与严重IAV感染相关的死亡方面并不完全有效。因此,有 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 限制与IAV感染相关的高全球医疗负担的药物。TIMP-1(组织抑制因子 金属蛋白酶1)控制基质金属蛋白酶(MMPs)的酶活性,众所周知 用于调节细胞外基质(ECM)的代谢,但其在IAV疾病发病机制中的贡献 没有得到深入的探索。我们新的初步数据显示,血浆TIMP-1水平显著 在确诊为甲型H1N1大流行性流感和季节性IAV感染的患者中上调,并且水平与 与PaO2/FiO2比值成反比。此外,我们的免疫荧光染色数据表明TIMP- 1在脂成纤维细胞中被显著诱导。与WT小鼠相比,TIMP-1-/-小鼠减少了H1N1禽流感病毒- 诱导体重减轻;死亡率;肺损伤;获得性免疫反应增强以及T细胞和B细胞 活化,减少毛细管渗漏。根据我们的数据,TIMP-1可能成为一种新的治疗靶点 在严重的IAV感染期间。本申请中提出的实验旨在1)识别规则和 TIMP-1在IAV感染中的作用;2)为TIMP-1的作用机制提供了新的见解 在IAV感染期间,缺乏可以提供更好的结果。这些研究的成功完成将为 未来研究新药(IND)的途径--使研究能够测试“一流”药物的安全性和有效性 针对宿主反应的治疗,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.
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Xiaoyun Wang其他文献

Xiaoyun Wang的其他文献

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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:
    10260933
  • 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:
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