Lipid peroxidation- and pyroptosis-induced tissue factor activation in pathogen-induced blood coagulation

病原体诱导的血液凝固中脂质过氧化和焦亡诱导的组织因子激活

基本信息

项目摘要

Project Summary/Abstract Tissue factor (TF), the primary initiator of the blood coagulation cascade, is carefully regulated to prevent aberrant coagulation activation. However, pathological conditions including bacterial and viral infection induce intravascular TF expression and lead to thrombosis. As TF-induced thrombosis is a major cause of acute myocardial infarction, ischemic stroke, and pulmonary embolism, improved understanding of the mechanisms of pathological TF activation may lead to new therapeutic targets. Pyroptosis, a form of inflammatory cell death, drives TF-mediated intravascular coagulation activation in bacterial sepsis. Emerging studies also implicate inflammasome activation in SARS-CoV-2 infection, but its role in TF activation is unknown. Our preliminary studies demonstrate that SARS-CoV-2 and specifically its accessory protein ORF3A induce TF activation in a phosphatidylserine (PS)-dependent mechanism that requires TMEM16F, similar to PS-dependent TF activation in pyroptosis. In Aim 1, we will investigate whether ORF3a-induced TF activation is driven by inflammasome- mediated pyroptosis. Lipid peroxidation and its highly reactive end products such as 4-hydroxy-2-nonenal (HNE) are involved in various forms of programmed cell death including pyroptosis. However, the role of HNE, the most stable and toxic reactive aldehyde produced during lipid peroxidation, in pyroptosis-associated TF and coagulation activation is not known. Our preliminary data showed that HNE induces PS-dependent TF activation in LPS-primed macrophages and causes intravascular coagulation activation in mice. However, the complete mechanism by which HNE induces PS externalization and TF activation is not known. In Aim 2, we will use chemical genetic approaches to dissect the mechanism of HNE-induced TF activation via pyroptosis in vitro and in vivo. Although lipid peroxidation plays a central role in cell death and coagulation activation in bacterial sepsis, a therapeutically targetable enzyme responsible for the unbridled lipid peroxidation and generation of pathological levels of reactive radicals such as HNE is not known. In Aim 3, we will use genetically modified mice deficient in lipid peroxidation and HNE formation to investigate TF-dependent pathologic coagulation activation and thrombosis during sepsis. A successful completion of these studies will help delineate a common pathway involved in pathologic TF activation across varied pathogenic infections and will also help identify a specific therapeutically targetable enzyme to attenuate TF activation in disease.
项目总结/摘要 组织因子(TF)是血液凝固级联反应的主要起始物, 异常凝血激活然而,包括细菌和病毒感染的病理条件诱导 血管内TF表达并导致血栓形成。由于TF诱导的血栓形成是急性血栓形成的主要原因, 心肌梗死、缺血性中风和肺栓塞,提高了对 病理性TF激活可能导致新的治疗靶点。焦亡,一种炎性细胞死亡, 在细菌性脓毒症中驱动TF介导的血管内凝血激活。新的研究还表明, SARS-CoV-2感染中炎性小体激活,但其在TF激活中的作用尚不清楚。我们的初步 研究表明,SARS-CoV-2和特别是其辅助蛋白ORF 3A诱导TF激活, 磷脂酰丝氨酸(PS)依赖性机制,需要TMEM 16 F,类似于PS依赖性TF激活 在焦亡中。在目的1中,我们将研究ORF 3a诱导的TF激活是否由炎性小体驱动。 介导的焦亡。脂质过氧化及其高反应性终产物,如4-羟基-2-壬烯醛(HNE) 参与各种形式的程序性细胞死亡,包括细胞凋亡。然而,HNE的作用,最 在脂质过氧化过程中产生的稳定和有毒的反应性醛,在热解相关的TF和 凝固活化是未知的。我们的初步数据表明,HNE诱导PS依赖的TF激活 在LPS引发的巨噬细胞中,并引起小鼠血管内凝血激活。然而,完整的 HNE诱导PS外化和TF激活的机制尚不清楚。在目标2中,我们将使用 化学遗传学方法来剖析HNE通过体外焦亡诱导TF活化的机制, in vivo.虽然脂质过氧化在细菌性脓毒症的细胞死亡和凝血激活中起着核心作用, 一种治疗靶向酶,负责无节制的脂质过氧化和产生 活性自由基如HNE的病理水平是未知的。在目标3中,我们将使用转基因小鼠 缺乏脂质过氧化和HNE形成,以研究TF依赖性病理性凝血激活 以及败血症时的血栓形成这些研究的成功完成将有助于描绘一个共同的途径 参与各种病原性感染的病理性TF激活,也将有助于确定一种特异性的 治疗靶向酶可减弱疾病中TF的激活。

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 }}

Shabbir Ahmed Ansari其他文献

Role of flavonoids in thrombotic, cardiovascular, and inflammatory diseases
  • DOI:
    10.1007/s10787-019-00612-6
  • 发表时间:
    2019-07-15
  • 期刊:
  • 影响因子:
    5.300
  • 作者:
    Cijo George Vazhappilly;Shabbir Ahmed Ansari;Rula Al-Jaleeli;Aya Mudhafar Al-Azawi;Wafaa S. Ramadan;Varsha Menon;Rawad Hodeify;Shoib Sarwar Siddiqui;Maxime Merheb;Rachel Matar;Rajan Radhakrishnan
  • 通讯作者:
    Rajan Radhakrishnan

Shabbir Ahmed Ansari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 }}

相似海外基金

Relationship between 4-Hydroxynonenal and Agitation Severity in Alzheimer’s Disease
4-羟基壬烯醛与阿尔茨海默病患者躁动严重程度之间的关系
  • 批准号:
    486589
  • 财政年份:
    2022
  • 资助金额:
    $ 16.45万
  • 项目类别:
    Studentship Programs
Investigating the role of red blood cells in oxidative stress and thrombogenesis - from 4-hydroxynonenal chemistry to mouse to man.
研究红细胞在氧化应激和血栓形成中的作用 - 从 4-羟基壬烯醛化学到小鼠再到人类。
  • 批准号:
    304797
  • 财政年份:
    2014
  • 资助金额:
    $ 16.45万
  • 项目类别:
    Operating Grants
Protein modification by 4-hydroxynonenal (HNE) modulates cell function: identification of specific proteins as cellular targets of HNE binding
4-羟基壬烯醛 (HNE) 的蛋白质修饰调节细胞功能:鉴定特定蛋白质作为 HNE 结合的细胞靶标
  • 批准号:
    341797-2010
  • 财政年份:
    2014
  • 资助金额:
    $ 16.45万
  • 项目类别:
    Discovery Grants Program - Individual
Protein modification by 4-hydroxynonenal (HNE) modulates cell function: identification of specific proteins as cellular targets of HNE binding
4-羟基壬烯醛 (HNE) 的蛋白质修饰调节细胞功能:鉴定特定蛋白质作为 HNE 结合的细胞靶标
  • 批准号:
    341797-2010
  • 财政年份:
    2013
  • 资助金额:
    $ 16.45万
  • 项目类别:
    Discovery Grants Program - Individual
Targeting colorectal cancer-initiating cells and anti-EGFR therapeutic resistance by manipulating levels of the reactive aldehyde, 4-hydroxynonenal.
通过控制活性醛 4-羟基壬烯醛的水平,靶向结直肠癌起始细胞和抗 EGFR 治疗耐药性。
  • 批准号:
    302201
  • 财政年份:
    2013
  • 资助金额:
    $ 16.45万
  • 项目类别:
    Salary Programs
Targeting colorectal cancer-initiating cells and anti-EGFR therapeutic resistance by manipulating levels of the reactive aldehyde, 4-hydroxynonenal
通过控制活性醛 4-羟基壬烯醛的水平,靶向结直肠癌起始细胞和抗 EGFR 治疗耐药性
  • 批准号:
    281581
  • 财政年份:
    2013
  • 资助金额:
    $ 16.45万
  • 项目类别:
    Operating Grants
The lipid peroxidation product 4-hydroxynonenal in the pathophysiology of osteoarthritis
脂质过氧化产物4-羟基壬烯醛在骨关节炎病理生理学中的作用
  • 批准号:
    286322
  • 财政年份:
    2013
  • 资助金额:
    $ 16.45万
  • 项目类别:
    Operating Grants
Role of 4-hydroxynonenal in n-6 polyunsaturated fatty acid induced cytoxicity in cardiac cells
4-羟基壬烯醛在 n-6 多不饱和脂肪酸诱导的心肌细胞细胞毒性中的作用
  • 批准号:
    427447-2012
  • 财政年份:
    2012
  • 资助金额:
    $ 16.45万
  • 项目类别:
    Postgraduate Scholarships - Master's
Protein modification by 4-hydroxynonenal (HNE) modulates cell function: identification of specific proteins as cellular targets of HNE binding
4-羟基壬烯醛 (HNE) 的蛋白质修饰调节细胞功能:鉴定特定蛋白质作为 HNE 结合的细胞靶标
  • 批准号:
    341797-2010
  • 财政年份:
    2012
  • 资助金额:
    $ 16.45万
  • 项目类别:
    Discovery Grants Program - Individual
Role of 4-hydroxynonenal in n-6 polyunsaturated fatty acid induced cytoxicity in cardiac cells
4-羟基壬烯醛在 n-6 多不饱和脂肪酸诱导的心肌细胞细胞毒性中的作用
  • 批准号:
    427447-2012
  • 财政年份:
    2012
  • 资助金额:
    $ 16.45万
  • 项目类别:
    Alexander Graham Bell Canada Graduate Scholarships - Master's
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了