Dys-regulation of the MnSOD-Ac-ROS-HIF2a axis promotes IR / Cisplatin resistance phenotype

MnSOD-Ac-ROS-HIF2a 轴的失调促进 IR/顺铂耐药表型

基本信息

  • 批准号:
    9262705
  • 负责人:
  • 金额:
    $ 39.65万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2017
  • 资助国家:
    美国
  • 起止时间:
    2017-04-01 至 2022-03-31
  • 项目状态:
    已结题

项目摘要

Summary - Metabolic stress, a hallmark of cancer, is an early event in tumorigenesis that accumulates in the cell from endogenous processes, exogenous conditions, and/or agents that induce oxidative stress. Additionally, the aberrant accumulation of reactive oxygen species (ROS), as well as altered mitochondrial metabolism (i.e., oxidative or metabolic stress), are early events in the process of cellular reprogramming that under specific conditions leads to tumor cell resistance. It has become increasingly clear that lysine acetylation (i.e., mitochondrial Acetylome) is the primary post-translational modification employed by the mitochondrial to sense changes in ROS and/or metabolic conditions and initial adaptive or reparative signaling processes, including metabolic reprogramming to maintain homeostatic poise. While a link between the dysregulation of the mitochondrial Acetylome, ROS detoxification (i.e., metabolic stress), and metabolic reprogramming leading to tumor cell resistance has long been suggested, rigorous mechanistic data to supporting this intriguing idea has been limited. In this grant application it is proposed that the acetylation status of manganese superoxide dismutase (MnSOD), a critical mitochondrial enzyme, directs detoxification activity as well as connects metabolic stress and mitochondrial reparative pathways that maintain metabolic fidelity. In this regard, it is proposed that MnSOD exhibits a dichotomous function, based on the acetylation status of K68, where the homotetrameric form acts as a protective detoxification enzyme against aberrant ROS levels. In contrast, K68 acetylation inhibits the homotetrameric complex and MnSOD subsequently forms a monomeric protein form that is proposed to function as an oncoprotein. Thus, it is proposed that the dysregulation MnSOD axis, due to acetylation, alters MnSOD function which subsequently reprograms mitochondria resulting in a tumor cell anti-cancer resistance therapy phenotype. In addition, targeted the acetylation status or restoring the MnSOD functions will be used to generate and validation of new therapeutic strategies to sensitize tumor cells to cytotoxic therapies
摘要-代谢应激是癌症的标志,是肿瘤发生的早期事件, 从内源性过程、外源性条件和/或 诱导氧化应激。此外,活性氧(ROS)的异常积累, 以及改变的线粒体代谢(即,氧化或代谢应激),是早期事件, 在特定条件下导致肿瘤细胞抗性的细胞重编程过程。 越来越清楚的是赖氨酸乙酰化(即,线粒体乙酰基组)是 线粒体用于感知ROS变化的初级翻译后修饰 和/或代谢状况和初始适应性或修复性信号传导过程,包括 代谢重编程以维持体内平衡。虽然调节失调与 线粒体乙酰组,ROS解毒(即,代谢应激)和代谢 导致肿瘤细胞抗性的重编程长期以来一直被认为是严格的机制, 支持这一有趣想法的数据有限。在这份补助金申请中,建议 线粒体关键酶锰超氧化物歧化酶(MnSOD)乙酰化状态 酶,指导解毒活动,以及连接代谢应激和线粒体 维持代谢保真度的修复途径。在这方面,建议MnSOD 基于K68的乙酰化状态,显示二分功能,其中同源四聚体 形式作为保护性解毒酶对抗异常的ROS水平。相比之下,K68 乙酰化抑制同源四聚体复合物和MnSOD随后形成单体 一种被认为起癌蛋白作用的蛋白质形式。因此,建议 由于乙酰化,MnSOD轴的失调改变了MnSOD的功能, 重编程线粒体,导致肿瘤细胞抗癌抗性治疗表型。在 此外,针对乙酰化状态或恢复MnSOD功能将用于产生 和验证使肿瘤细胞对细胞毒性疗法敏感的新治疗策略

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 }}

David Gius其他文献

David Gius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('David Gius', 18)}}的其他基金

Lineage Plasticity, due to Disruption of MnSOD Biology, drives resistance to Ionizing Radiation / Androgen Deprivation Therapy
由于 MnSOD 生物学的破坏,谱系可塑性驱动了对电离辐射/雄激素剥夺疗法的抵抗
  • 批准号:
    10737810
  • 财政年份:
    2021
  • 资助金额:
    $ 39.65万
  • 项目类别:
Lineage Plasticity, due to Disruption of MnSOD Biology, drives resistance to Ionizing Radiation / Androgen Deprivation Therapy
由于 MnSOD 生物学的破坏,谱系可塑性驱动了对电离辐射/雄激素剥夺疗法的抵抗
  • 批准号:
    10533472
  • 财政年份:
    2021
  • 资助金额:
    $ 39.65万
  • 项目类别:
Lineage Plasticity, due to Disruption of MnSOD Biology, drives resistance to Ionizing Radiation / Androgen Deprivation Therapy
由于 MnSOD 生物学的破坏,谱系可塑性驱动了对电离辐射/雄激素剥夺疗法的抵抗
  • 批准号:
    10390451
  • 财政年份:
    2021
  • 资助金额:
    $ 39.65万
  • 项目类别:
MnSOD-K68-Ac reprograms a lineage plasticity switch / stemness in ER+ breast malignancies
MnSOD-K68-Ac 重新编程 ER 乳腺恶性肿瘤中的谱系可塑性开关/干性
  • 批准号:
    10327336
  • 财政年份:
    2021
  • 资助金额:
    $ 39.65万
  • 项目类别:
MnSOD-K68-Ac reprograms a lineage plasticity switch / stemness in ER+ breast malignancies.
MnSOD-K68-Ac 重新编程 ER 乳腺恶性肿瘤中的谱系可塑性开关/干性。
  • 批准号:
    10817556
  • 财政年份:
    2021
  • 资助金额:
    $ 39.65万
  • 项目类别:
Dys-regulation of the MnSOD-Ac-ROS-HIF2a axis promotes IR / Cisplatin resistance phenotype
MnSOD-Ac-ROS-HIF2a 轴的失调促进 IR/顺铂耐药表型
  • 批准号:
    10335424
  • 财政年份:
    2021
  • 资助金额:
    $ 39.65万
  • 项目类别:
MnSOD-K68-Ac reprograms a lineage plasticity switch / stemness in ER+ breast malignancies
MnSOD-K68-Ac 重新编程 ER 乳腺恶性肿瘤中的谱系可塑性开关/干性
  • 批准号:
    10541193
  • 财政年份:
    2021
  • 资助金额:
    $ 39.65万
  • 项目类别:
Lineage Plasticity, due to Disruption of MnSOD Biology, drives resistance to Ionizing Radiation / Androgen Deprivation Therapy
由于 MnSOD 生物学的破坏,谱系可塑性驱动了对电离辐射/雄激素剥夺疗法的抵抗
  • 批准号:
    10548835
  • 财政年份:
    2021
  • 资助金额:
    $ 39.65万
  • 项目类别:
Dys-regulation of the MnSOD-Ac-ROS-HIF2a axis promotes IR / Cisplatin resistance phenotype
MnSOD-Ac-ROS-HIF2a 轴的失调促进 IR/顺铂耐药表型
  • 批准号:
    10024964
  • 财政年份:
    2017
  • 资助金额:
    $ 39.65万
  • 项目类别:
Dys-regulation of the MnSOD-Ac-ROS-HIF2a axis promotes IR / Cisplatin resistance phenotype
MnSOD-Ac-ROS-HIF2a 轴的失调促进 IR/顺铂耐药表型
  • 批准号:
    9889066
  • 财政年份:
    2017
  • 资助金额:
    $ 39.65万
  • 项目类别:

相似海外基金

Rational design of rapidly translatable, highly antigenic and novel recombinant immunogens to address deficiencies of current snakebite treatments
合理设计可快速翻译、高抗原性和新型重组免疫原,以解决当前蛇咬伤治疗的缺陷
  • 批准号:
    MR/S03398X/2
  • 财政年份:
    2024
  • 资助金额:
    $ 39.65万
  • 项目类别:
    Fellowship
Re-thinking drug nanocrystals as highly loaded vectors to address key unmet therapeutic challenges
重新思考药物纳米晶体作为高负载载体以解决关键的未满足的治疗挑战
  • 批准号:
    EP/Y001486/1
  • 财政年份:
    2024
  • 资助金额:
    $ 39.65万
  • 项目类别:
    Research Grant
CAREER: FEAST (Food Ecosystems And circularity for Sustainable Transformation) framework to address Hidden Hunger
职业:FEAST(食品生态系统和可持续转型循环)框架解决隐性饥饿
  • 批准号:
    2338423
  • 财政年份:
    2024
  • 资助金额:
    $ 39.65万
  • 项目类别:
    Continuing Grant
Metrology to address ion suppression in multimodal mass spectrometry imaging with application in oncology
计量学解决多模态质谱成像中的离子抑制问题及其在肿瘤学中的应用
  • 批准号:
    MR/X03657X/1
  • 财政年份:
    2024
  • 资助金额:
    $ 39.65万
  • 项目类别:
    Fellowship
CRII: SHF: A Novel Address Translation Architecture for Virtualized Clouds
CRII:SHF:一种用于虚拟化云的新型地址转换架构
  • 批准号:
    2348066
  • 财政年份:
    2024
  • 资助金额:
    $ 39.65万
  • 项目类别:
    Standard Grant
BIORETS: Convergence Research Experiences for Teachers in Synthetic and Systems Biology to Address Challenges in Food, Health, Energy, and Environment
BIORETS:合成和系统生物学教师的融合研究经验,以应对食品、健康、能源和环境方面的挑战
  • 批准号:
    2341402
  • 财政年份:
    2024
  • 资助金额:
    $ 39.65万
  • 项目类别:
    Standard Grant
The Abundance Project: Enhancing Cultural & Green Inclusion in Social Prescribing in Southwest London to Address Ethnic Inequalities in Mental Health
丰富项目:增强文化
  • 批准号:
    AH/Z505481/1
  • 财政年份:
    2024
  • 资助金额:
    $ 39.65万
  • 项目类别:
    Research Grant
ERAMET - Ecosystem for rapid adoption of modelling and simulation METhods to address regulatory needs in the development of orphan and paediatric medicines
ERAMET - 快速采用建模和模拟方法的生态系统,以满足孤儿药和儿科药物开发中的监管需求
  • 批准号:
    10107647
  • 财政年份:
    2024
  • 资助金额:
    $ 39.65万
  • 项目类别:
    EU-Funded
Ecosystem for rapid adoption of modelling and simulation METhods to address regulatory needs in the development of orphan and paediatric medicines
快速采用建模和模拟方法的生态系统,以满足孤儿药和儿科药物开发中的监管需求
  • 批准号:
    10106221
  • 财政年份:
    2024
  • 资助金额:
    $ 39.65万
  • 项目类别:
    EU-Funded
Recite: Building Research by Communities to Address Inequities through Expression
背诵:社区开展研究,通过表达解决不平等问题
  • 批准号:
    AH/Z505341/1
  • 财政年份:
    2024
  • 资助金额:
    $ 39.65万
  • 项目类别:
    Research Grant
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了