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
- 来源:
- 关键词:AcetylationAddressAffectAgarAllograftingApplications GrantsBiochemistryCell physiologyCellsCellular biologyChemical ExposureCisplatinComplexCytotoxic ChemotherapyDataDeacetylationDrug Metabolic DetoxicationEnzymesEquilibriumEventExhibitsGeneticGenomic InstabilityGrowthIn VitroIonizing radiationLaboratoriesLeadLinkLysineMalignant NeoplasmsMetabolicMetabolic stressMethodsMitochondriaModelingModificationMolecular BiologyMusOncogenicOncoproteinsOxidative StressPathway interactionsPeroxidasesPhenotypePhysiologicalPost-Translational Protein ProcessingProcessProtein AcetylationProteinsRadiation exposureRadioresistanceReactive Oxygen SpeciesResearch ProposalsResistanceRoleSOD2 geneSeriesSignal TransductionSiteSuperoxidesTechniquesTherapeuticTumor Suppressor ProteinsTumor stageValidationXenograft ModelXenograft procedurebasechemotherapeutic agentdensityin vivoinnovationknock-downmimeticsmitochondrial metabolismmouse modelmutantneoplastic cellnovel therapeutic interventionoverexpressionpermissivenesspreventradioresistanttargeted treatmenttissue/cell culturetumortumor initiationtumorigenesis
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:代谢应激是癌症的一个标志,是肿瘤发生的早期事件
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)
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David Gius其他文献
David Gius的其他文献
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{{ 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:
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:
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:
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:
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:
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