Lipid Metabolism-driven Drug Resistance in Multiple Myeloma
脂质代谢驱动的多发性骨髓瘤耐药性
基本信息
- 批准号:10334473
- 负责人:
- 金额:$ 3.19万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-01-18 至 2024-04-06
- 项目状态:已结题
- 来源:
- 关键词:AcidsAcyl Coenzyme AAdipocytesAdipose tissueAdultAffectAgeAgingApoptosisBiological AssayBone MarrowCancerousCarbon DioxideCarnitine Palmitoyltransferase ICell CountCell LineCell ProliferationCell SurvivalCellsCellular AssayCessation of lifeCoculture TechniquesCoenzyme A LigasesDataDevelopmentDexamethasoneDrug resistanceEnergy-Generating ResourcesEnzymesEpidemiologyFatty AcidsFatty acid glycerol estersGene ExpressionGeneticGlucocorticoidsGoalsGrowthHumanHypertrophyHypoxiaIn VitroIncidenceIncubatedLabelLinkLipidsMalignant - descriptorMalignant NeoplasmsMarrowMass Spectrum AnalysisMeasuresMesenchymalMetabolic PathwayMetabolismMethodsMultiple MyelomaNonesterified Fatty AcidsObesityOleatesOutputOxidative StressPharmacologyPhenotypePlasmaPlasma CellsProcessProductionReactive Oxygen SpeciesResistanceRespirationRiskRisk FactorsRoleSerumSignal TransductionSilkSourceSupporting CellSurvival RateTestingTissue EngineeringVisceralWorkYellow Marrowadipocyte differentiationadipokinesbasebiological adaptation to stressbone cellcancer cellchemotherapeutic agentchemotherapycytokineexperimental studyfatty acid metabolismfatty acid oxidationhigh body mass indexinnovationinsightknock-downlipid metabolismmigrationneoplastic cellnovelobese personobesity riskprogenitorprotein expressionresponsesmall hairpin RNAstemsubcutaneousthree dimensional cell culturetreatment responsetriacsin Ctumor microenvironmenttwo-dimensional
项目摘要
Abstract
Multiple myeloma (MM) is characterized by the expansion of malignant plasma cells primarily in the bone
marrow and has a 5-year survival rate of only 50%. Obesity increases the risk of MM incidence and predicts a
poorer response to treatment. In fact, obesity is a major risk factor for many cancers, and there are likely an
array of mechanisms by which obesity supports cancer development and progression. One mechanism may
be through the increased availability of free fatty acids, which are elevated in the plasma of obese people.
Fatty acids can be used as a fuel source for cells through a process called fatty acid oxidation. Thus, based on
the role of fatty acid oxidation in other cancers, and the obesity risk factor in MM, we hypothesize that fatty
acids and fatty acid oxidation contribute to MM progression. Myeloma cells are supported by many factors and
cells in the bone marrow microenvironment. Interestingly, up to 70% of the bone marrow is composed of yellow
(fatty) marrow, which is increased in obesity, as well as aging (another major risk factor for MM). Yellow
marrow is composed of bone marrow adipocytes (fat cells), which are often adjacent to myeloma cells. Our lab,
and others, have shown that bone marrow adipocytes drive resistance to chemotherapeutic agents in myeloma
cells. Thus, we will test the hypothesis that fatty acid oxidation contributes to myeloma cell survival and drug
resistance, and that bone marrow adipocytes support myeloma cell drug resistance through increasing their
fatty acid oxidation, in the following two Aims. Aim 1) We will test the hypothesis that fatty acid oxidation
supports myeloma cells by inhibiting the rate-limiting enzyme for fatty acid oxidation, carnitine-
palmitoyltransferase 1 (CPT1), through genetic or pharmacological methods, and measuring myeloma cell
proliferation/death, respiration, metabolites, and responses to dexamethasone. To specifically test the roles of
certain lipids in fatty acid oxidation, we will investigate the changes in myeloma cell survival and drug
resistance in response to lipids that are highly enriched in human serum and from bone marrow adipocytes.
Aim 2) We will test the hypothesis that bone marrow adipocytes enhance myeloma cell fatty acid oxidation,
survival, and drug resistance by co-culturing myeloma cells lacking functional CPT1 as above, or controls, with
bone marrow adipocytes and identifying how myeloma cells respond and metabolize bone marrow adipocyte-
derived fatty acids. Taken together, these experiments will elucidate the mechanisms of how bone marrow
adipocytes and fatty acid oxidation affect myeloma cell survival and drug resistance.
摘要
项目成果
期刊论文数量(0)
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Connor Murphy其他文献
Connor Murphy的其他文献
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{{ truncateString('Connor Murphy', 18)}}的其他基金
Lipid Metabolism-driven Drug Resistance in Multiple Myeloma
脂质代谢驱动的多发性骨髓瘤耐药性
- 批准号:
10596472 - 财政年份:2021
- 资助金额:
$ 3.19万 - 项目类别:
Lipid Metabolism-driven Drug Resistance in Multiple Myeloma
脂质代谢驱动的多发性骨髓瘤耐药性
- 批准号:
10154064 - 财政年份:2021
- 资助金额:
$ 3.19万 - 项目类别:
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