"MerTK Cleavage and Signaling in Atherosclerosis"

“动脉粥样硬化中的 MerTK 裂解和信号转导”

基本信息

  • 批准号:
    9120607
  • 负责人:
  • 金额:
    $ 50.81万
  • 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:
    2016-03-15 至 2020-02-29
  • 项目状态:
    已结题

项目摘要

 DESCRIPTION (provided by applicant): A critical goal in heart research is to elucidate the mechanisms that promote clinically significant atherosclerosis and then use this knowledge to design novel therapies. The overarching concept that a form the basis of this proposal is that plaque progression represents a pathologic process called defective inflammation resolution. The proposal is based on strong in vitro and in vivo data supporting a critical role for the macrophage (Mf) MerTK receptor in the resolution response--a response that goes awry in advanced atherosclerosis. MerTK enables Mfs to carry out efferocytosis, a critical resolving process in atherosclerosis, and to promote the synthesis of specialized pro-resolving mediators (SPMs), including lipoxin A4 (LXA4) and resolvin D1 (RvD1). Moreover, in inflammatory settings including in advanced atherosclerotic lesions, MerTK is destroyed by ADAM17-mediated cleavage. We propose that this process compromises both efferocytosis and the synthesis of SPMs, leading to the progression of the type of necrotic, inflammatory plaques that, in humans, are clinically dangerous. In this proposal, Aim 1 will further explore the hypothesis that MerTK signals an inflammation resolution response in Mfs, and that MerTK cleavage in atherosclerosis compromises resolution and promotes plaque progression. We will investigate the mechanisms linking MerTK signaling to SPM synthesis and then test the importance of MerTK cleavage in defective efferocytosis, defective mediator synthesis, and plaque progression in atherosclerosis by comparing WD-fed MertkWT Ldlr-/- mice with MertkCR Ldlr-/- mice, which is a unique model in which endogenous Mertk has been replaced by a fully functional cleavage-resistance Mertk. Aim 2 will explore the regulation of MerTK cleavage by athero-relevant factors and SPMs, both in vitro and in atherosclerosis. We will address several hypotheses as to how athero-relevant factors promote ADAM17-mediated MerTK cleavage and, based on new data, how SPMs suppress MerTK cleavage. At the conclusion of this project, we hope to have elucidated new mechanistic links between inflammation resolution and atherosclerosis, which could provide the basis for new drugs that block plaque progress in high-risk humans. Atherothrombotic vascular disease is the leading cause of death in the industrialized world, with global spread predicted for the future. Important mechanistic and therapeutic gaps exist in combatting this disease. This proposal will study mechanisms that promote atherosclerosis progression in a manner that has the potential to be highly translatable to human therapy through the use of pro-resolving therapy.
 描述(由适用提供):心脏研究的关键目标是阐明促进临床上重要的动脉粥样硬化的机制,然后使用这些知识来设计新型疗法。总体概念是该提案的基础是斑块进展代表一种称为缺陷感染分辨率的病理过程。该提案基于强大的体外和体内数据,支持巨噬细胞(MF)MERTK受体在分辨率响应中的关键作用 - 这种反应在晚期动脉粥样硬化中出现了问题。 MERTK使MFS能够在动脉粥样硬化中进行传染性吞噬作用,这是一个关键的解决过程,并促进了专门的促促介体(SPM)的综合,包括脂氧蛋白A4(LXA4)和Resolvin D1(RVD1)。此外,在包括晚期动脉粥样硬化病变在内的炎症环境中,MERTK被ADAM17介导的裂解破坏。我们建议这一过程损害了肾上腺增多症和SPM的合成,从而导致坏死性,炎性斑块的发展,而在人类中,这种斑块在临床上是危险的。在该提案中,AIM 1将进一步探讨MERTK在MFS中的注射分辨率响应的假设,而动脉粥样硬化中的MERTK裂解会损害分辨率并促进斑块进展。 We will investigate the mechanisms linking MerTK signaling to SPM Synthesis and then test the importance of MerTK cleavage in defective efferocytosis, defective mediator synthesis, and plaque progression in atherosclerosis by comparing WD-fed MertkWT Ldlr-/- mice with MertkCR Ldlr-/- mice, which is a unique model in which endogenous Mertk has been replaced by功能齐全的切割抵抗力MERTK。 AIM 2将探索与动脉省相关的因素和SPMS对MERTK裂解的调节,在体外,我们将解决有关动脉粥样硬化因素如何促进ADAM17介导的MERTK裂解以及基于新数据,SPMS抑制MERTK CLEAVAGE的几种假设。在该项目的结束时,我们希望阐明炎症解决方案和动脉粥样硬化之间的新机械联系,这可以为阻止高风险人类斑块进展的新药物提供基础。动脉瘤血栓性血管疾病是工业化世界中死亡的主要原因,全球差异预计 未来。对抗这种疾病的重要机械和治疗差距存在。该提案将研究以一种有可能通过使用促分解治疗来高度翻译为人类治疗的方式来促进动脉粥样硬化进展的机制。

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)

暂无数据

数据更新时间:2024-06-01

Ira A Tabas的其他基金

A Mechanistic and Translational Research Program Linking Impaired Resolution, Defective Efferocytosis, and Clonal Hematopoiesis to the Formation of Clinically Dangerous Atherosclerotic Plaques
一项将分辨率受损、胞吞作用缺陷和克隆造血与临床危险动脉粥样硬化斑块形成联系起来的机制和转化研究项目
  • 批准号:
    9889165
    9889165
  • 财政年份:
    2019
  • 资助金额:
    $ 50.81万
    $ 50.81万
  • 项目类别:
A Mechanistic and Translational Research Program Linking Impaired Resolution, Defective Efferocytosis, and Clonal Hematopoiesis to the Formation of Clinically Dangerous Atherosclerotic Plaques
一项将分辨率受损、胞吞作用缺陷和克隆造血与临床危险动脉粥样硬化斑块形成联系起来的机制和转化研究项目
  • 批准号:
    10339421
    10339421
  • 财政年份:
    2019
  • 资助金额:
    $ 50.81万
    $ 50.81万
  • 项目类别:
A Mechanistic and Translational Research Program Linking Impaired Resolution, Defective Efferocytosis, and Clonal Hematopoiesis to the Formation of Clinically Dangerous Atherosclerotic Plaques
一项将分辨率受损、胞吞作用缺陷和克隆造血与临床危险动脉粥样硬化斑块形成联系起来的机制和转化研究项目
  • 批准号:
    10565956
    10565956
  • 财政年份:
    2019
  • 资助金额:
    $ 50.81万
    $ 50.81万
  • 项目类别:
A Mechanistic and Translational Research Program Linking Impaired Resolution, Defective Efferocytosis, and Clonal Hematopoiesis to the Formation of Clinically Dangerous Atherosclerotic Plaques
一项将分辨率受损、胞吞作用缺陷和克隆造血与临床危险动脉粥样硬化斑块形成联系起来的机制和转化研究项目
  • 批准号:
    10112953
    10112953
  • 财政年份:
    2019
  • 资助金额:
    $ 50.81万
    $ 50.81万
  • 项目类别:
Autophagy in Advanced Atherosclerosis
晚期动脉粥样硬化中的自噬
  • 批准号:
    8023974
    8023974
  • 财政年份:
    2011
  • 资助金额:
    $ 50.81万
    $ 50.81万
  • 项目类别:
Autophagy in Advanced Atherosclerosis
晚期动脉粥样硬化中的自噬
  • 批准号:
    8383465
    8383465
  • 财政年份:
    2011
  • 资助金额:
    $ 50.81万
    $ 50.81万
  • 项目类别:
Autophagy in Advanced Atherosclerosis
晚期动脉粥样硬化中的自噬
  • 批准号:
    8575545
    8575545
  • 财政年份:
    2011
  • 资助金额:
    $ 50.81万
    $ 50.81万
  • 项目类别:
Autophagy in Advanced Atherosclerosis
晚期动脉粥样硬化中的自噬
  • 批准号:
    8208979
    8208979
  • 财政年份:
    2011
  • 资助金额:
    $ 50.81万
    $ 50.81万
  • 项目类别:
Mechanisms of Defective Efferocytosis in Atherosclerosis
动脉粥样硬化中细胞作用缺陷的机制
  • 批准号:
    8389888
    8389888
  • 财政年份:
    2011
  • 资助金额:
    $ 50.81万
    $ 50.81万
  • 项目类别:
Mechanisms of Defective Efferocytosis in Atherosclerosis
动脉粥样硬化中细胞作用缺陷的机制
  • 批准号:
    8575547
    8575547
  • 财政年份:
    2011
  • 资助金额:
    $ 50.81万
    $ 50.81万
  • 项目类别:

相似国自然基金

时空序列驱动的神经形态视觉目标识别算法研究
  • 批准号:
    61906126
  • 批准年份:
    2019
  • 资助金额:
    24.0 万元
  • 项目类别:
    青年科学基金项目
本体驱动的地址数据空间语义建模与地址匹配方法
  • 批准号:
    41901325
  • 批准年份:
    2019
  • 资助金额:
    22.0 万元
  • 项目类别:
    青年科学基金项目
大容量固态硬盘地址映射表优化设计与访存优化研究
  • 批准号:
    61802133
  • 批准年份:
    2018
  • 资助金额:
    23.0 万元
  • 项目类别:
    青年科学基金项目
IP地址驱动的多径路由及流量传输控制研究
  • 批准号:
    61872252
  • 批准年份:
    2018
  • 资助金额:
    64.0 万元
  • 项目类别:
    面上项目
针对内存攻击对象的内存安全防御技术研究
  • 批准号:
    61802432
  • 批准年份:
    2018
  • 资助金额:
    25.0 万元
  • 项目类别:
    青年科学基金项目

相似海外基金

Climate Change Effects on Pregnancy via a Traditional Food
气候变化通过传统食物对怀孕的影响
  • 批准号:
    10822202
    10822202
  • 财政年份:
    2024
  • 资助金额:
    $ 50.81万
    $ 50.81万
  • 项目类别:
Leveraging COVID-19 to modernize depression care for VA primary care populations
利用 COVID-19 实现 VA 初级保健人群的抑郁症护理现代化
  • 批准号:
    10636681
    10636681
  • 财政年份:
    2023
  • 资助金额:
    $ 50.81万
    $ 50.81万
  • 项目类别:
Establishment of a Bat Resource for Infectious Disease Research
建立用于传染病研究的蝙蝠资源
  • 批准号:
    10495114
    10495114
  • 财政年份:
    2023
  • 资助金额:
    $ 50.81万
    $ 50.81万
  • 项目类别:
Targeting Alcohol-Opioid Co-Use Among Young Adults Using a Novel MHealth Intervention
使用新型 MHealth 干预措施针对年轻人中酒精与阿片类药物的同时使用
  • 批准号:
    10456380
    10456380
  • 财政年份:
    2023
  • 资助金额:
    $ 50.81万
    $ 50.81万
  • 项目类别:
Immunomodulatory ligand B7-1 targets p75 neurotrophin receptor in neurodegeneration
免疫调节配体 B7-1 在神经变性中靶向 p75 神经营养蛋白受体
  • 批准号:
    10660332
    10660332
  • 财政年份:
    2023
  • 资助金额:
    $ 50.81万
    $ 50.81万
  • 项目类别: