Targeting the Inflammasome to Prevent Thoracic Aortic Aneurysms and Dissections

针对炎症小体预防胸主动脉瘤和夹层

基本信息

  • 批准号:
    9247885
  • 负责人:
  • 金额:
    $ 39.63万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2016
  • 资助国家:
    美国
  • 起止时间:
    2016-09-01 至 2020-06-30
  • 项目状态:
    已结题

项目摘要

 DESCRIPTION (provided by applicant): Ascending thoracic aortic aneurysms and dissections (ATAAD) are interrelated cardiovascular diseases that carry high mortality.] Current approaches to pharmacologic prevention of ATAAD are ineffective, particularly in patients with sporadic disease. Although there is a critical need to develop new treatment strategies, a major barrier to this goal is a poor understanding of the molecular mechanisms that trigger and then promote aortic degeneration in sporadic ATAAD. Therefore, our long-term goal is to improve the under- standing of the pathobiology of aortic wall degeneration in hope of developing new pharmacological strategies to prevent ATAAD formation and progression. The overall objective of this application is to systematically define the role of the NLRP3 inflammasome cascade, a multiprotein platform involved in amplifying intracellular stress responses, in promoting aortic destruction and the extent to which this cascade represents a therapeutic target against ATAAD. The central hypotheses are: (1) the NLRP3-ASC-caspase-1 cascade promotes aortic degeneration by promoting smooth muscle cell contractile dysfunction and aortic destruction, and (2) treatment with pharmacological inhibitors of this cascade will prevent ATAAD. These central hypotheses will be tested through three specific aims, each of which focuses on specific hypotheses based on our preliminary data. [In the first aim, we will seek to prove our hypothesis that the NLRP3- ASC-caspase-1 inflammasome cascade promotes ascending aortic wall inflammatory cell infiltration, matrix destruction, contractile dysfunction, and biomechanical failure through a series of experiments with a mouse model of sporadic ATAAD. In the second aim, we will seek to prove the hypothesis that the inflammasome cascade directly cleaves and degrades myosin heavy chain and tropomyosin, and thus promotes SMC contractile dysfunction. We will also determine whether intracellular stress activates the inflammasome cascade and confirm the association of intracellular stress and the inflammasome in human ATAAD tissue. In the third aim, we will test the hypothesis that NLRP3 inhibitors (glyburide, parthenolide and MCC950) will prevent ascending aortic destruction and disease progression in our mouse model of sporadic ATAAD.] The proposed research is significant because it will determine how the inflammasome cascade is activated, how this cascade promotes ATAAD development, and the extent to which an inflammasome inhibitor can prevent ATAAD. This research is innovative because it represents a new and substantive departure from the status quo, namely the current pharmacologic approaches to preventing aortic disease progression. The development of a new, effective pharmacological prevention strategy would have an important positive effect on disease prognosis by delaying or obviating invasive procedures in patients presenting with early-stage ascending aortic disease, suppressing disease progression in patients who are poor candidates for surgical treatment, and improving the durability of surgical aortic repairs.
 描述(由申请人提供):胸升主动脉瘤和夹层(ATAAD)是相关的心血管疾病,死亡率高。]目前药物预防ATAAD的方法无效,特别是在散发性疾病患者中。尽管迫切需要开发新的治疗策略,但实现这一目标的主要障碍是对触发并促进散发性ATAAD主动脉变性的分子机制的理解不足。因此,我们的长期目标是提高对主动脉壁退行性变病理生物学的理解,以期开发新的药理学策略来预防ATAAD的形成和进展。本申请的总体目标是系统地定义NLRP 3炎性体级联(一种参与放大细胞内应激反应的多蛋白平台)在促进主动脉破坏中的作用,以及该级联代表针对ATAAD的治疗靶标的程度。核心假设是:(1)NLRP 3-ASC-半胱天冬酶-1级联通过促进平滑肌细胞收缩功能障碍和主动脉破坏而促进主动脉变性,和(2)用该级联的药理学抑制剂治疗将预防ATAAD。这些中心假设将通过三个具体目标进行测试,每个目标都侧重于基于我们初步数据的特定假设。[In第一个目标,我们将通过一系列散发性ATAAD小鼠模型的实验,试图证明我们的假设,即NLRP 3- ASC-caspase-1炎性级联反应促进升主动脉壁炎性细胞浸润、基质破坏、收缩功能障碍和生物力学失效。在第二个目标中,我们将试图证明这一假设,即炎性级联反应直接切割和降解肌球蛋白重链和原肌球蛋白,从而促进SMC收缩功能障碍。我们还将确定细胞内应激是否激活炎性体级联反应,并确认细胞内应激与人ATAAD组织中炎性体的相关性。在第三个目标中,我们将测试NLRP 3抑制剂(格列本脲、帕塞农肽和MCC 950)将在我们的散发性ATAAD小鼠模型中预防升主动脉破坏和疾病进展的假设。这项研究意义重大,因为它将确定炎性体级联反应如何被激活,该级联反应如何促进ATAAD的发展,以及炎性体抑制剂可以在多大程度上预防ATAAD。这项研究是创新的,因为它代表了一个新的和实质性的偏离现状,即目前的药理学方法,以防止主动脉疾病的进展。开发一种新的、有效的药物预防策略将通过延迟或避免早期升主动脉疾病患者的侵入性手术、抑制不适合手术治疗的患者的疾病进展以及提高主动脉外科修复术的耐久性,对疾病预后产生重要的积极影响。

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 }}

SCOTT A LEMAIRE其他文献

SCOTT A LEMAIRE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('SCOTT A LEMAIRE', 18)}}的其他基金

Pro-inflammatory Pyroptotic Cell Death in Aortic Degeneration
主动脉变性中的促炎焦亡细胞死亡
  • 批准号:
    10643934
  • 财政年份:
    2021
  • 资助金额:
    $ 39.63万
  • 项目类别:
Pro-inflammatory Pyroptotic Cell Death in Aortic Degeneration
主动脉变性中的促炎焦亡细胞死亡
  • 批准号:
    10435503
  • 财政年份:
    2021
  • 资助金额:
    $ 39.63万
  • 项目类别:
Pro-inflammatory Pyroptotic Cell Death in Aortic Degeneration
主动脉变性中的促炎焦亡细胞死亡
  • 批准号:
    10237565
  • 财政年份:
    2021
  • 资助金额:
    $ 39.63万
  • 项目类别:
Mitochondrial Damage-Induced Necroptotic Cell Death in SporadicAscending Thoracic Aortic Aneurysms and Dissections
散发性升主动脉瘤和夹层中线粒体损伤诱导的坏死性细胞死亡
  • 批准号:
    9980977
  • 财政年份:
    2018
  • 资助金额:
    $ 39.63万
  • 项目类别:
Mitochondrial Damage-Induced Necroptotic Cell Death in SporadicAscending Thoracic Aortic Aneurysms and Dissections
散发性升主动脉瘤和夹层中线粒体损伤诱导的坏死性细胞死亡
  • 批准号:
    9765053
  • 财政年份:
    2018
  • 资助金额:
    $ 39.63万
  • 项目类别:
Mitochondrial Damage-Induced Necroptotic Cell Death in SporadicAscending Thoracic Aortic Aneurysms and Dissections
散发性升主动脉瘤和夹层中线粒体损伤诱导的坏死性细胞死亡
  • 批准号:
    10239058
  • 财政年份:
    2018
  • 资助金额:
    $ 39.63万
  • 项目类别:
Targeting ER Stress To Treat Aortic Aneurysms and Dissections
针对内质网应激治疗主动脉瘤和夹层
  • 批准号:
    9338945
  • 财政年份:
    2016
  • 资助金额:
    $ 39.63万
  • 项目类别:
Targeting ER stress to Treat Aortic Aneurysms and Dissections
针对内质网应激治疗主动脉瘤和夹层
  • 批准号:
    9081997
  • 财政年份:
    2016
  • 资助金额:
    $ 39.63万
  • 项目类别:
Targeting the Inflammasome to Prevent Thoracic Aortic Aneurysms and Dissections
针对炎症小体预防胸主动脉瘤和夹层
  • 批准号:
    9130437
  • 财政年份:
    2015
  • 资助金额:
    $ 39.63万
  • 项目类别:
NATIONAL REGISTRY OF GENETICALLY TRIGGERED THORACIC AORTIC ANEURYSMS
国家基因触发胸主动脉瘤登记处
  • 批准号:
    8356739
  • 财政年份:
    2010
  • 资助金额:
    $ 39.63万
  • 项目类别:

相似海外基金

RII Track-4:NSF: From the Ground Up to the Air Above Coastal Dunes: How Groundwater and Evaporation Affect the Mechanism of Wind Erosion
RII Track-4:NSF:从地面到沿海沙丘上方的空气:地下水和蒸发如何影响风蚀机制
  • 批准号:
    2327346
  • 财政年份:
    2024
  • 资助金额:
    $ 39.63万
  • 项目类别:
    Standard Grant
BRC-BIO: Establishing Astrangia poculata as a study system to understand how multi-partner symbiotic interactions affect pathogen response in cnidarians
BRC-BIO:建立 Astrangia poculata 作为研究系统,以了解多伙伴共生相互作用如何影响刺胞动物的病原体反应
  • 批准号:
    2312555
  • 财政年份:
    2024
  • 资助金额:
    $ 39.63万
  • 项目类别:
    Standard Grant
How Does Particle Material Properties Insoluble and Partially Soluble Affect Sensory Perception Of Fat based Products
不溶性和部分可溶的颗粒材料特性如何影响脂肪基产品的感官知觉
  • 批准号:
    BB/Z514391/1
  • 财政年份:
    2024
  • 资助金额:
    $ 39.63万
  • 项目类别:
    Training Grant
Graduating in Austerity: Do Welfare Cuts Affect the Career Path of University Students?
紧缩毕业:福利削减会影响大学生的职业道路吗?
  • 批准号:
    ES/Z502595/1
  • 财政年份:
    2024
  • 资助金额:
    $ 39.63万
  • 项目类别:
    Fellowship
Insecure lives and the policy disconnect: How multiple insecurities affect Levelling Up and what joined-up policy can do to help
不安全的生活和政策脱节:多种不安全因素如何影响升级以及联合政策可以提供哪些帮助
  • 批准号:
    ES/Z000149/1
  • 财政年份:
    2024
  • 资助金额:
    $ 39.63万
  • 项目类别:
    Research Grant
感性個人差指標 Affect-X の構築とビスポークAIサービスの基盤確立
建立个人敏感度指数 Affect-X 并为定制人工智能服务奠定基础
  • 批准号:
    23K24936
  • 财政年份:
    2024
  • 资助金额:
    $ 39.63万
  • 项目类别:
    Grant-in-Aid for Scientific Research (B)
How does metal binding affect the function of proteins targeted by a devastating pathogen of cereal crops?
金属结合如何影响谷类作物毁灭性病原体靶向的蛋白质的功能?
  • 批准号:
    2901648
  • 财政年份:
    2024
  • 资助金额:
    $ 39.63万
  • 项目类别:
    Studentship
ERI: Developing a Trust-supporting Design Framework with Affect for Human-AI Collaboration
ERI:开发一个支持信任的设计框架,影响人类与人工智能的协作
  • 批准号:
    2301846
  • 财政年份:
    2023
  • 资助金额:
    $ 39.63万
  • 项目类别:
    Standard Grant
Investigating how double-negative T cells affect anti-leukemic and GvHD-inducing activities of conventional T cells
研究双阴性 T 细胞如何影响传统 T 细胞的抗白血病和 GvHD 诱导活性
  • 批准号:
    488039
  • 财政年份:
    2023
  • 资助金额:
    $ 39.63万
  • 项目类别:
    Operating Grants
How motor impairments due to neurodegenerative diseases affect masticatory movements
神经退行性疾病引起的运动障碍如何影响咀嚼运动
  • 批准号:
    23K16076
  • 财政年份:
    2023
  • 资助金额:
    $ 39.63万
  • 项目类别:
    Grant-in-Aid for Early-Career Scientists
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了