Selective S-nitrosation of mitochondrial complex I by MitoSNO as a new therapy for cardiac ischaemia-reperfusion injury

MitoSNO 选择性 S-亚硝化线粒体复合物 I 作为心脏缺血再灌注损伤的新疗法

基本信息

  • 批准号:
    MC_EX_MR/M015769/1
  • 负责人:
  • 金额:
    $ 100.71万
  • 依托单位:
  • 依托单位国家:
    英国
  • 项目类别:
    Research Grant
  • 财政年份:
    2015
  • 资助国家:
    英国
  • 起止时间:
    2015 至 无数据
  • 项目状态:
    已结题

项目摘要

Ischaemia-reperfusion (IR) injury underlies many clinically important conditions, such as heart attack and stroke. Ischaemia occurs when the blood supply to an organ is interrupted, for example by a blood clot. If the blood supply is restored the tissue can recover. However, reperfusion of the ischaemic organ with oxygenated blood leads to extensive tissue damage that worsens the long-term prognosis for the patient. This injury is initiated largely by the production of damaging free radicals from mitochondria during reperfusion that leads to cell death. We have developed a novel mitochondria-targeted drug called MitoSNO that prevents free radical production from mitochondria during IR injury. MitoSNO comprises a lipophilic cation that drives its rapid and extensive uptake into mitochondria within the heart immediately following its intravenous injection during reperfusion of the ischaemic organ. Within mitochondria MitoSNO selectively transfers a nitric oxide moiety onto a particular cysteine on respiratory complex I, thereby preventing the mitochondrial free radical production that normally occurs during reperfusion. This modification is reversed after 5-10 mins allowing the mitochondria to return to full activity. Rodent studies have shown that MitoSNO prevents cardiac IR injury in clinically relevant in vivo models, thereby greatly enhancing the long-term recovery of heart function. MitoSNO is unique as no other protective therapies can be applied to organs at reperfusion to block mitochondrial free radical production. In this study MitoSNO will be assessed to see if it is also protective against IR injury in pigs in preparation for a first-in-man Phase I study. As similar IR injury is found in other situations, such as heart attack and organ transplantation, MitoSNO may also prove a useful therapeutic for a range of indications.
缺血再灌注(IR)损伤是许多临床重要疾病的基础,如心脏病发作和中风。当器官的血液供应被中断时,例如被血凝块中断,就会发生缺血。如果血液供应恢复,组织可以恢复。然而,用含氧血液对缺血器官进行再灌注会导致广泛的组织损伤,这会影响患者的长期预后。这种损伤主要是由再灌注过程中线粒体产生的破坏性自由基引起的,导致细胞死亡。我们已经开发了一种新的靶向药物MitoSNO,可以防止IR损伤期间线粒体产生自由基。MitoSNO包含亲脂性阳离子,其在缺血器官的再灌注期间在其静脉内注射后立即驱动其快速且广泛地摄取到心脏内的线粒体中。在线粒体内,MitoSNO选择性地将一氧化氮部分转移到呼吸复合物I上的特定半胱氨酸上,从而防止再灌注期间通常发生的线粒体自由基产生。这种修饰在5-10分钟后逆转,使线粒体恢复完全活性。啮齿动物研究表明,MitoSNO在临床相关的体内模型中预防心脏IR损伤,从而大大增强心脏功能的长期恢复。MitoSNO是独特的,因为没有其他保护性疗法可以应用于再灌注时的器官以阻断线粒体自由基的产生。在这项研究中,将评估MitoSNO,以确定它是否也能保护猪免受IR损伤,为首次人体I期研究做准备。由于在其他情况下发现了类似的IR损伤,例如心脏病发作和器官移植,MitoSNO也可以证明是一系列适应症的有用治疗剂。

项目成果

期刊论文数量(7)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Mitochondrial thiol modification by a targeted electrophile inhibits metabolism in breast adenocarcinoma cells by inhibiting enzyme activity and protein levels.
  • DOI:
    10.1016/j.redox.2016.01.002
  • 发表时间:
    2016-08
  • 期刊:
  • 影响因子:
    11.4
  • 作者:
    Smith MR;Vayalil PK;Zhou F;Benavides GA;Beggs RR;Golzarian H;Nijampatnam B;Oliver PG;Smith RA;Murphy MP;Velu SE;Landar A
  • 通讯作者:
    Landar A
Acute regional changes in myocardial strain may predict ventricular remodelling after myocardial infarction in a large animal model.
  • DOI:
    10.1038/s41598-021-97834-y
  • 发表时间:
    2021-09-15
  • 期刊:
  • 影响因子:
    4.6
  • 作者:
    Mansell DS;Bruno VD;Sammut E;Chiribiri A;Johnson T;Khaliulin I;Lopez DB;Gill HS;Fraser KH;Murphy M;Krieg T;Suleiman MS;George S;Ascione R;Cookson AN
  • 通讯作者:
    Cookson AN
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Michael Murphy其他文献

Beyond Physicalism: Toward Reconciliation of Science and Spirituality
超越物理主义:科学与灵性的调和
  • DOI:
  • 发表时间:
    2015
  • 期刊:
  • 影响因子:
    0
  • 作者:
    H. Atmanspacher;Loriliai Biernacki;B. Carr;W. Fach;M. Grosso;Michael Murphy;D. Presti;G. Shaw;H. Stapp;Eric M. Weiss;I. Whicher
  • 通讯作者:
    I. Whicher
Fast track open aortic surgery: reduced post operative stay with a goal directed pathway.
快速通道开放主动脉手术:通过目标导向途径减少术后停留时间。
Averting catastrophic outcomes: the fundamentals of “impossible” airways
避免灾难性后果:“不可能”气道的基本原理
Not part of my routine: a qualitative study of use and understanding of UV forecast information and the SunSmart app
不是我日常工作的一部分:对紫外线预报信息和 SunSmart 应用程序的使用和理解的定性研究
  • DOI:
  • 发表时间:
    2019
  • 期刊:
  • 影响因子:
    4.5
  • 作者:
    Anna Nicholson;Michael Murphy;Heather Walker;R. Tinker;S. Dobbinson
  • 通讯作者:
    S. Dobbinson
The ESDQ: A New Method of Assessing Emotional and Social Dysfunction in Patients Following Brain Surgery
ESDQ:评估脑手术后患者情绪和社交功能障碍的新方法

Michael Murphy的其他文献

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{{ truncateString('Michael Murphy', 18)}}的其他基金

Collaborative Research: Filling in the Central Himalayan Seismic Gap: A Structural, Neotectonic, and Paleoseismic Investigation of the Western Nepal Fault System
合作研究:填补喜马拉雅中部地震间隙:尼泊尔西部断层系的构造、新构造和古地震研究
  • 批准号:
    1827863
  • 财政年份:
    2018
  • 资助金额:
    $ 100.71万
  • 项目类别:
    Standard Grant
Mitochondrial oxidative damage and human diseases
线粒体氧化损伤与人类疾病
  • 批准号:
    MC_UU_00015/3
  • 财政年份:
    2017
  • 资助金额:
    $ 100.71万
  • 项目类别:
    Intramural
MRI: Acquisition of a Computing Cluster for Atmospheric and Geophysical Research
MRI:获取用于大气和地球物理研究的计算集群
  • 批准号:
    1624068
  • 财政年份:
    2016
  • 资助金额:
    $ 100.71万
  • 项目类别:
    Standard Grant
Developing chemical mass spectrometry probes to assess the production of reactive oxygen species in vivo
开发化学质谱探针来评估体内活性氧的产生
  • 批准号:
    BB/I012923/1
  • 财政年份:
    2011
  • 资助金额:
    $ 100.71万
  • 项目类别:
    Research Grant
The Deformation History of the India-Asia Suture Zone, Lopukangri Rift, South-Central Tibet
西藏中南部洛布岗日裂谷印亚缝合带的变形历史
  • 批准号:
    0711527
  • 财政年份:
    2007
  • 资助金额:
    $ 100.71万
  • 项目类别:
    Continuing Grant
Modelling Needs and Resources of Older People to 2030
到 2030 年老年人的需求和资源建模
  • 批准号:
    ES/D004640/1
  • 财政年份:
    2007
  • 资助金额:
    $ 100.71万
  • 项目类别:
    Research Grant
Behavioral and Endocrine Predictors of Reproductive Success in a Cryptically Polygamous Passerine Bird
神秘的一夫多妻制雀形目鸟类繁殖成功的行为和内分泌预测因素
  • 批准号:
    0639370
  • 财政年份:
    2007
  • 资助金额:
    $ 100.71万
  • 项目类别:
    Continuing Grant
The American Proust: American Art and Culture in A la recherche du temps perdu
美国普鲁斯特:追忆逝去的美国艺术与文化
  • 批准号:
    112801/1
  • 财政年份:
    2006
  • 资助金额:
    $ 100.71万
  • 项目类别:
    Research Grant
Collaborative Research: Investigation of Syncollisional Extension and Basin Development in the High Himalaya
合作研究:喜马拉雅高山同步碰撞伸展和盆地发育调查
  • 批准号:
    0438826
  • 财政年份:
    2005
  • 资助金额:
    $ 100.71万
  • 项目类别:
    Continuing Grant
Geological Investigation of the Juncture between the Western and Southern Margins of the Tibetan Plateau
青藏高原西缘与南缘交界处地质调查
  • 批准号:
    0106808
  • 财政年份:
    2001
  • 资助金额:
    $ 100.71万
  • 项目类别:
    Standard Grant

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Mitochondrial Dynamics in Brain TumorInitiating Cells
脑肿瘤起始细胞的线粒体动力学
  • 批准号:
    9759836
  • 财政年份:
    2017
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