Therapeutic efficacies of neutrophil elastase and RIP1 inhibitors in acute lung injury

中性粒细胞弹性蛋白酶和RIP1抑制剂治疗急性肺损伤的疗效

基本信息

  • 批准号:
    10311120
  • 负责人:
  • 金额:
    $ 23.18万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2020
  • 资助国家:
    美国
  • 起止时间:
    2020-12-02 至 2023-05-31
  • 项目状态:
    已结题

项目摘要

5. Project Summary/Abstract Acute lung injury (ALI) is a syndrome of respiratory failure characterized by protein-rich pulmonary edema that causes severe hypoxemia and labored breathing. In the United States, the annual incidence of ALI is about 200,000 with a mortality rate of 30-40%; yet, there is no FDA-approved pharmacological therapy for ALI. Neutrophils are the most abundant circulating white blood cells in the human body and provide the first line of defense against invading pathogens. In the lung, while neutrophils are essential for pathogen elimination, exuberant accumulation and prolonged survival of neutrophils in the interstitial and alveolar spaces contribute to ALI by releasing a variety of injurious molecules, including neutrophil elastase (NE), metalloproteases, reactive oxygen species (ROS), and other proteolytic enzymes. Although all these injurious molecules contribute to ALI, an increasing body of studies have demonstrated that NE is the most potent hydrolytic enzyme that plays a key role in lung alveolar injury, and that inhibition of NE with small molecular inhibitors [e.g. Sivelestat (Siv)] reduces measures of lung injury and inflammation in animal models of ALI. However, clinical studies have not yet provided a clear consensus. Whereas in Japanese phase III clinical trials, Siv improved pulmonary functions, in North American multicenter studies, Siv rather increased long-term mortality by unknown mechanisms. Thus, identification of molecular events associated with adverse effects of Siv in ALI is an important task for the development of novel and combination treatment regimens. Recently, in unbiased functional protease purification experiments, we discovered that NE cleaves receptor interacting protein 1 (RIP1), and that inhibition of NE with Siv leads to RIP1-dependent necroptosis in mouse and human neutrophils following treatment with lipopolysaccharide (LPS) or TNFα. Such RIP1-induced necroptosis can be inhibited by RIP1 kinase inhibitors (e.g. Nec-1s) or knockout (KO) of RIP3. We found that LPS/Siv-induced necroptosis was significantly inhibited in RIP3 KO neutrophils. Importantly, in a mouse model of ALI induced by 50% lethal dose of LPS, Siv in combination with Nec-1s resulted in 90% survival of the mice (P=0.001), whereas neither Siv nor Nec-1s alone afforded significant protection against the death. Thus, we hypothesize that inhibition of NE with Siv in ALI leads to RIP1-mediated necroptosis in neutrophils, which causes secondary inflammation and lung injury, and that inhibition of RIP1-mediated necroptosis significantly improves the effectiveness of NE inhibitors in ALI. Aim-1. Determine the therapeutic efficacies of RIP1 and NE inhibitors in lung injury and inflammation using mouse models of ALI. Aim-2. Determine how genetic ablation of NE or RIP3 affects lung injury and inflammation in ALI mice.
5. 项目总结/文摘

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 }}

HASEM HABELHAH其他文献

HASEM HABELHAH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('HASEM HABELHAH', 18)}}的其他基金

The roles of TRAF2 and RIP1 in breast cancer cell survival
TRAF2 和 RIP1 在乳腺癌细胞存活中的作用
  • 批准号:
    10363270
  • 财政年份:
    2022
  • 资助金额:
    $ 23.18万
  • 项目类别:
The roles of TRAF2 and RIP1 in breast cancer cell survival
TRAF2 和 RIP1 在乳腺癌细胞存活中的作用
  • 批准号:
    10619506
  • 财政年份:
    2022
  • 资助金额:
    $ 23.18万
  • 项目类别:
HtrA2-mediated RIP1 cleavage regulates neuronal inflammation and death
HtrA2介导的RIP1裂解调节神经元炎症和死亡
  • 批准号:
    9371476
  • 财政年份:
    2017
  • 资助金额:
    $ 23.18万
  • 项目类别:
RIP1 Cleavage by Caspase-8 is Essential for TRAIL-induced NF-kB Activation
Caspase-8 裂解 RIP1 对于 TRAIL 诱导的 NF-kB 激活至关重要
  • 批准号:
    8033152
  • 财政年份:
    2010
  • 资助金额:
    $ 23.18万
  • 项目类别:
RIP1 Cleavage by Caspase-8 is Essential for TRAIL-induced NF-kB Activation
Caspase-8 对 RIP1 的切割对于 TRAIL 诱导的 NF-kB 激活至关重要
  • 批准号:
    8403529
  • 财政年份:
    2010
  • 资助金额:
    $ 23.18万
  • 项目类别:
RIP1 Cleavage by Caspase-8 is Essential for TRAIL-induced NF-kB Activation
Caspase-8 裂解 RIP1 对于 TRAIL 诱导的 NF-kB 激活至关重要
  • 批准号:
    7887290
  • 财政年份:
    2010
  • 资助金额:
    $ 23.18万
  • 项目类别:
RIP1 Cleavage by Caspase-8 is Essential for TRAIL-induced NF-kB Activation
Caspase-8 裂解 RIP1 对于 TRAIL 诱导的 NF-kB 激活至关重要
  • 批准号:
    8206767
  • 财政年份:
    2010
  • 资助金额:
    $ 23.18万
  • 项目类别:
Regulation of TRAF2 Activity in Normal and Tumor Cells
正常细胞和肿瘤细胞中 TRAF2 活性的调节
  • 批准号:
    7339874
  • 财政年份:
    2006
  • 资助金额:
    $ 23.18万
  • 项目类别:
Regulation of TRAF2 Activity in Normal and Tumor Cells
正常细胞和肿瘤细胞中 TRAF2 活性的调节
  • 批准号:
    7187428
  • 财政年份:
    2006
  • 资助金额:
    $ 23.18万
  • 项目类别:
Regulation of TRAF2 Activity in Normal and Tumor Cells
正常细胞和肿瘤细胞中 TRAF2 活性的调节
  • 批准号:
    7034445
  • 财政年份:
    2006
  • 资助金额:
    $ 23.18万
  • 项目类别:

相似海外基金

Combinatorial cytokine-coated macrophages for targeted immunomodulation in acute lung injury
组合细胞因子包被的巨噬细胞用于急性肺损伤的靶向免疫调节
  • 批准号:
    10648387
  • 财政年份:
    2023
  • 资助金额:
    $ 23.18万
  • 项目类别:
Lung epithelial cell-derived C3 in acute lung injury
肺上皮细胞衍生的 C3 在急性肺损伤中的作用
  • 批准号:
    10720687
  • 财政年份:
    2023
  • 资助金额:
    $ 23.18万
  • 项目类别:
Examining the role of TRMT1 and tRNA methylation in acute lung injury and ARDS
检查 TRMT1 和 tRNA 甲基化在急性肺损伤和 ARDS 中的作用
  • 批准号:
    10719249
  • 财政年份:
    2023
  • 资助金额:
    $ 23.18万
  • 项目类别:
Inducible HMGB1 antagonist for viral-induced acute lung injury.
诱导型 HMGB1 拮抗剂,用于治疗病毒引起的急性肺损伤。
  • 批准号:
    10591804
  • 财政年份:
    2023
  • 资助金额:
    $ 23.18万
  • 项目类别:
MAP2K1 AND MAP2K2 IN ACUTE LUNG INJURY AND RESOLUTION
MAP2K1 和 MAP2K2 在急性肺损伤中的作用及缓解
  • 批准号:
    10741574
  • 财政年份:
    2023
  • 资助金额:
    $ 23.18万
  • 项目类别:
Development of a new treatment for COVID-19-related acute lung injury targeting the microbiota-derived peptide corisin
针对微生物群衍生肽 corisin 开发治疗 COVID-19 相关急性肺损伤的新疗法
  • 批准号:
    23K07651
  • 财政年份:
    2023
  • 资助金额:
    $ 23.18万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Probing immunovascular mechanobiology in pneumonia-associated acute lung injury at the single capillary level
在单毛细血管水平探讨肺炎相关急性肺损伤的免疫血管力学生物学
  • 批准号:
    10679944
  • 财政年份:
    2023
  • 资助金额:
    $ 23.18万
  • 项目类别:
The amyloid precursor protein protects against acute lung injury
淀粉样前体蛋白可预防急性肺损伤
  • 批准号:
    10575258
  • 财政年份:
    2023
  • 资助金额:
    $ 23.18万
  • 项目类别:
Role of macrophages and miRNA in regulating lung macrophage polarization and lung pathogenesis during respiratory virus-induced acute lung injury in normal and diabetic Syrian hamsters.
正常和糖尿病叙利亚仓鼠呼吸道病毒引起的急性肺损伤期间巨噬细胞和 miRNA 在调节肺巨噬细胞极化和肺部发病机制中的作用。
  • 批准号:
    10701207
  • 财政年份:
    2023
  • 资助金额:
    $ 23.18万
  • 项目类别:
Identification of novel phenotypes of acute lung injury using multimodal longitudinal data
使用多模态纵向数据识别急性肺损伤的新表型
  • 批准号:
    MR/Y000404/1
  • 财政年份:
    2023
  • 资助金额:
    $ 23.18万
  • 项目类别:
    Fellowship
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了