Investigation of NRF2-Dependent Metabolic Liabilities
NRF2 依赖性代谢负担的研究
基本信息
- 批准号:10582332
- 负责人:
- 金额:$ 37.15万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-07-01 至 2025-06-30
- 项目状态:未结题
- 来源:
- 关键词:AgarAmino AcidsAntioxidantsApplications GrantsBiologyCRISPR/Cas technologyCancer CenterCancer ModelCancer PatientCancer cell lineCellsCysteineCysteine Metabolism PathwayCysteine dioxygenaseCystineDataEngineeringEnzymesGenetic EngineeringGenetically Engineered MouseGenetsGlutamatesGlutathioneGlycineGoalsGrowthHumanInvestigationKnock-in MouseLung AdenocarcinomaLung CapacityLung NeoplasmsMaintenanceMalignant neoplasm of lungMediatingMetabolicMetabolic ControlMetabolismMethylationModelingMutant Strains MiceMutationNatureNon-Small-Cell Lung CarcinomaOutcomeOxidation-ReductionOxidative StressPathway interactionsPatientsPositioning AttributeProcessProductionProliferatingProteinsReactionRoleSamplingSpecimenSulfitesSulfurSystemTXN geneTaurineTestingTherapeutic InterventionToxic effectWorkXenograft Modelcancer therapycysteine sulfinatedisulfide bondepigenetic silencinghypotaurinein vivo Modellung cancer celllung tumorigenesismetabolomicsmouse modelmutantneoplastic cellnovelparent grantprotein expressionresponserestorationtargeted treatmenttranscription factortumortumor initiationtumorigenesisuptake
项目摘要
Metabolic reprogramming occurs during tumorigenesis and holds promise for cancer therapy. However, the
underlying mechanisms that control these metabolic alterations and their contribution to tumor maintenance
are generally lacking. Mutations in NRF2 and its negative regulator KEAP1 are found in 15-34% of non-small
cell lung cancer (NSCLC) and lead to constitutive NRF2 activity. Many NRF2-regulated processes center on
the production and utilization of the antioxidant glutathione, which is synthesized from the amino acids
cysteine, glycine and glutamate. In our previous work, we found that glutathione synthesis was critical for the
pro-proliferative effects of NRF2 during tumor initiation. Furthermore, we found that NRF2 promotes metabolic
rewiring to increase glycine availability to support glutathione synthesis. To define how constitutive NRF2
activity induces metabolic reprogramming to support GSH synthesis, we generated genetically engineered,
conditional knock-in mouse models of the cancer mutations NRF2D29H and KEAP1R554Q. Our preliminary
analysis of NRF2-regulated metabolism indicates that cysteine dioxygenase (CDO1) limits glutathione
production by NRF2, produces toxic byproducts, and is silenced during tumorigenesis. We have established a
metabolomics platform for the analysis of sulfur-containing metabolites, and a genetically engineered NRF2
and KEAP1 mutant lung cancer mouse models for in vivo studies and are now poised to define the tumor
suppressive role of CDO1 and its metabolites during lung tumorigenesis.
In Aim 1 we will examine the whether CDO1 antagonizes the NRF2-regulated antioxidant response by
depleting cysteine.
In Aim 2 we will examine the selective toxicity of CDO1 expression to cells with NRF2 activity due to toxic
byproduct production.
In Aim 3 we will examine whether CDO1 loss promotes lung tumorigenesis using our genetically engineered
KEAP1 and NRF2 mutant mouse lung tumor models and patient tumor samples.
The ultimate goal and the overall impact of this project are to characterize CDO1 as a novel metabolic liability
for tumors with NRF2/KEAP1 mutations in order to define opportunities for therapeutic intervention for patients
with these mutations, which currently lack targeted therapy.
代谢重编程发生在肿瘤发生期间,并为癌症治疗带来希望。但
控制这些代谢改变的潜在机制及其对肿瘤维持的贡献
普遍缺乏。在15-34%的非小细胞肺癌中发现了NRF 2及其负调节因子KEAP 1的突变。
细胞肺癌(NSCLC),并导致组成型NRF 2活性。许多NRF 2调节的过程集中在
以氨基酸为原料合成的抗氧化剂谷胱甘肽的生产和利用
半胱氨酸、甘氨酸和谷氨酸。在我们以前的工作中,我们发现谷胱甘肽的合成对于
NRF 2在肿瘤起始期间的促增殖作用。此外,我们发现NRF 2促进代谢,
重新连接以增加甘氨酸的可用性以支持谷胱甘肽的合成。为了确定组成型NRF 2
活性诱导代谢重编程以支持GSH合成,我们产生了基因工程,
癌症突变NRF 2D 29 H和KEAP 1 R554 Q的条件性敲入小鼠模型。我们的初步
NRF 2调节代谢的分析表明,半胱氨酸双加氧酶(CDO 1)限制谷胱甘肽
NRF 2的产生,产生有毒的副产物,并在肿瘤发生过程中沉默。我们建立了
用于含硫代谢物分析的代谢组学平台,以及基因工程NRF 2
和KEAP 1突变肺癌小鼠模型进行体内研究,现在准备定义肿瘤
CDO 1及其代谢产物在肺肿瘤发生中的抑制作用
在目的1中,我们将通过以下方式来检测CDO 1是否拮抗NRF 2调节的抗氧化反应:
耗尽半胱氨酸。
在目的2中,我们将检查CDO 1表达对具有NRF 2活性的细胞的选择性毒性,这是由于毒性的细胞毒性。
副产品生产。
在目标3中,我们将使用我们的基因工程方法来检查CDO 1缺失是否促进肺肿瘤发生。
KEAP 1和NRF 2突变小鼠肺肿瘤模型和患者肿瘤样品。
该项目的最终目标和总体影响是将CDO 1描述为一种新的代谢倾向
对于NRF 2/KEAP 1突变的肿瘤,以确定患者治疗干预的机会
这些突变目前缺乏靶向治疗。
项目成果
期刊论文数量(3)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Quantification and Tracing of Stable Isotope into Cysteine and Glutathione.
半胱氨酸和谷胱甘肽稳定同位素的定量和追踪。
- DOI:10.1007/978-1-0716-3247-5_5
- 发表时间:2023
- 期刊:
- 影响因子:0
- 作者:Kang,YunPyo;DeNicola,GinaM
- 通讯作者:DeNicola,GinaM
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Gina Marie DeNicola其他文献
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{{ truncateString('Gina Marie DeNicola', 18)}}的其他基金
Metabolic basis of the NADPH-independent disulfide reductase system in mouse liver
小鼠肝脏中不依赖 NADPH 的二硫键还原酶系统的代谢基础
- 批准号:
10056616 - 财政年份:2020
- 资助金额:
$ 37.15万 - 项目类别:
Metabolic basis of the NADPH-independent disulfide reductase system in mouse liver
小鼠肝脏中不依赖 NADPH 的二硫键还原酶系统的代谢基础
- 批准号:
10263357 - 财政年份:2020
- 资助金额:
$ 37.15万 - 项目类别:
Metabolic basis of the NADPH-independent disulfide reductase system in mouse liver
小鼠肝脏中不依赖 NADPH 的二硫键还原酶系统的代谢基础
- 批准号:
10473813 - 财政年份:2020
- 资助金额:
$ 37.15万 - 项目类别:
Metabolic basis of the NADPH-independent disulfide reductase system in mouse liver
小鼠肝脏中不依赖 NADPH 的二硫键还原酶系统的代谢基础
- 批准号:
10005545 - 财政年份:2019
- 资助金额:
$ 37.15万 - 项目类别:
Investigation of NRF2-Dependent Metabolic Liabilities
NRF2 依赖性代谢负担的研究
- 批准号:
10427369 - 财政年份:2018
- 资助金额:
$ 37.15万 - 项目类别:
Investigation of NRF2-Dependent Metabolic Liabilities
NRF2 依赖性代谢负担的研究
- 批准号:
10207542 - 财政年份:2018
- 资助金额:
$ 37.15万 - 项目类别:
Investigation of NRF2-Dependent Metabolic Liabilities
NRF2 依赖性代谢负担的研究
- 批准号:
10411427 - 财政年份:2018
- 资助金额:
$ 37.15万 - 项目类别:
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