Mechanistically Dissecting Glycolysis Regulation by Lactate and Its Therapeutic Potential in Cancer
机械剖析乳酸的糖酵解调节及其在癌症中的治疗潜力
基本信息
- 批准号:10745359
- 负责人:
- 金额:$ 24.9万
- 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:2023-01-01 至 2025-12-31
- 项目状态:未结题
- 来源:
- 关键词:ATP Synthesis PathwayAcuteAntidiabetic DrugsBiochemicalBiochemistryBioenergeticsBiological AssayBiomassCancer cell lineCarbonCell ProliferationCellsChemicalsCitric Acid CycleClinicalComplexConsumptionDataDevelopment PlansDoctor of PhilosophyElectron TransportEnvironmentEnzymesEquilibriumFDA approvedGeneticGlucoseGlycolysisGoalsGrowthImageIn VitroKnock-outKnowledgeLaboratory ResearchMalignant NeoplasmsMass Spectrum AnalysisMediatingMemorial Sloan-Kettering Cancer CenterMentorshipMetabolicMetabolismMethodsMitochondriaNutrientOrganellesOxidative PhosphorylationPermeabilityPhenforminPhosphorylation InhibitionPhysiciansPostdoctoral FellowProductionProliferatingProteinsPyruvateRegulationReporterResearchScientistSerumSourceTherapeuticTrainingUniversitiesWarburg Effectaerobic glycolysiscancer cellcancer therapycareer developmentclinical trainingdesignextracellularimaging modalityin vivoinhibitorinsightliquid chromatography mass spectrometrymedical schoolsmetabolomicsnoveloxidationpatient derived xenograft modelresearch and developmentresponseskillstumortumor metabolismtumor microenvironment
项目摘要
PROJECT SUMMARY/ABSTRACT
Glucose is an essential fuel for cancer cell proliferation in serving both as a substrate for ATP production and
as an irreplaceable carbon source for biomass accumulation. Cancer cells are especially addicted to glucose
but only to secrete the majority as lactate (known as aerobic glycolysis or Warburg effect), thereby creating an
inhospitable glucose-poor and lactate-rich microenvironment that would otherwise be lethal to most cells.
However, cancer cells can efficiently use the limiting glucose and excess lactate for unlimited growth through
unclear mechanisms. My preliminary data revealed that in low glucose conditions, extracellular lactate
enhances cancer cell proliferation. Mechanistically, I found that lactate preferentially enters the mitochondria
TCA cycle over glucose to increase oxidative phosphorylation (OXPHOS) activity, which in turn suppresses
glycolysis to conserve extracellular glucose, suggesting cancer cells rely on lactate-induced OXPHOS for
optimal growth. The proposed studies are aimed at mechanistically dissecting the metabolic interplay between
lactate-mediated mitochondrial OXPHOS and glycolysis (Aim 1 & 3), and assessing therapeutic potential of
targeting lactate oxidation in cancer (Aim 2). The following specific aims are being pursued: Aim 1. Determine
how lactate-mediated increase in OXPHOS suppress glycolysis; Aim 2. Assess the in vivo therapeutic
potential of targeting lactate oxidation using Phenformin; Aim 3. Mechanistically dissect how cells distinguish
and preferentially use extracellular lactate over glucose for entry into TCA cycle. The knowledge and scientific
expertise gained through these studies will facilitate my transition to independence, with my long-term goal to
study and target metabolic vulnerabilities in cancer as a physician scientist.
In addition to the scientific goals, I have also outlined a detailed career development plan in this application to
obtain skills that are necessary for leading an independent research laboratory. The proposed research and
training plan will be conducted under the mentorship of Dr. Craig Thompson. Memorial Sloan-Kettering
Cancer Center, along with the nearby Rockefeller University and Weill Cornell Medical College will provide the
ideal academic environment to achieve these goals for me to transition to independence.
项目总结/文摘
项目成果
期刊论文数量(0)
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{{ truncateString('Xin Cai', 18)}}的其他基金
Mechanistically Dissecting Glycolysis Regulation by Lactate and Its Therapeutic Potential in Cancer
机械剖析乳酸的糖酵解调节及其在癌症中的治疗潜力
- 批准号:
10115324 - 财政年份:2021
- 资助金额:
$ 24.9万 - 项目类别:
Mechanistically Dissecting Glycolysis Regulation by Lactate and Its Therapeutic Potential in Cancer
机械剖析乳酸的糖酵解调节及其在癌症中的治疗潜力
- 批准号:
10352397 - 财政年份:2021
- 资助金额:
$ 24.9万 - 项目类别:
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