Investigation of Sirt1 activation to target IDH mutant glioma
Sirt1 激活针对 IDH 突变神经胶质瘤的研究
基本信息
- 批准号:10301538
- 负责人:
- 金额:$ 19.73万
- 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:2021-08-01 至 2026-07-31
- 项目状态:未结题
- 来源:
- 关键词:AdultAdult GliomaAffectAwardBiologyBrain NeoplasmsCDK4 geneCDKN2A geneCaloric RestrictionCell CycleCell Cycle InhibitionCell physiologyCellsCessation of lifeCharacteristicsChemotherapy and/or radiationClinical TrialsClustered Regularly Interspaced Short Palindromic RepeatsCoenzymesCollaborationsCommunitiesComplementCyclin-Dependent Kinase Inhibitor 2ADNA DamageDataDeacetylaseDementiaDiabetes MellitusDiagnosisDietDiet ModificationDietary InterventionDiseaseEffectivenessEnvironmentEnzymesEpigenetic ProcessExhibitsFrequenciesFundingFutureGeneral HospitalsGenerationsGenesGeneticGenetic TranscriptionGlioblastomaGliomaGlucoseGoalsGrantGrowthHallmark CellHeterogeneityHumanImplantIn VitroIntermittent fastingInvestigationIsocitrate DehydrogenaseLeadLongevityMalignant - descriptorMalignant NeoplasmsMassachusettsMentorsMetabolicMetabolismMethodsModelingMutationNeurologicNeurologyNeuronsNutrientOperative Surgical ProceduresPathway interactionsPatientsPhenotypePhysiciansPopulationPositioning AttributePre-Clinical ModelPrimary Brain NeoplasmsProcessProductionPrognosisProliferatingPublishingRecurrenceRecurrent diseaseReportingResearchResearch PersonnelResistanceSIRT1 geneScientistSignal TransductionTechniquesTestingTimeTissuesTrainingTranslatingUp-RegulationWorkXenograft procedureaggressive therapyanticancer researchbasecancer cellcancer therapycareer developmentclinically relevantcytotoxicitydesigndietary restrictioneffectiveness evaluationefficacy evaluationepigenomicsexperiencegain of function mutationgenotoxicityin vitro Modelin vivoinhibitor/antagonistinstructorinterestmedical schoolsmetabolomicsmiddle agemouse modelmutantneoplastic cellneuro-oncologynovel therapeuticsoverexpressionprematurepreventprogramsprotective effectresponseside effectsmall moleculetraittranscriptome sequencingtranscriptomicstranslational research programtreatment strategytumortumor eradicationtumor growthtumor metabolismyoung adult
项目摘要
Project Summary
IDH mutant gliomas are incurable, primary brain tumors that affect young to middle-aged adults and are
defined by a mutation in a key metabolic gene. Despite treatment with surgery, radiation and chemotherapy,
these gliomas exhibit unrelenting growth that ultimately leads to neurologic decline and premature death.
Interestingly, many types of tumor cells, including IDH mutant glioma, reprogram metabolic processes to promote
tumor growth. The overarching goal of this proposal is to target tumor-specific metabolic vulnerabilities to more
effectively halt IDH mutant glioma growth. This is based on preliminary data demonstrating that activation of the
critical metabolic regulator Sirt1, using Sirt1 activating compounds (STACs) or Sirt1 overexpression, leads to
cytotoxicity in IDH mutant cells, leading to the hypothesis that IDH mutant glioma sensitivity to Sirt1 activation is
related to IDH-induced metabolic rewiring. This five-year career development project is aimed at investigating
the metabolic underpinnings and effectiveness Sirt1 activation in IDH mutant gliomas using orthotopic mouse
models. This study will also determine the effectiveness of combining metabolic targeting with inhibition of the
cell cycle, a strategy based on the premise that targeting both processes may achieve more effective tumor
eradication. The first aim will test the anti-tumor effectiveness of STACs in combination with cell cycle inhibition
using patient-derived, IDH mutant glioma lines implanted intracerebrally. The second aim will utilize RNA-
sequencing to investigate the cellular processes influenced by STACs. The third aim will explore the ability of
caloric restriction, known to exert longevity-promoting effects through Sirt1 upregulation, to enhance cell cycle
inhibition and prevent glioma growth.
Dr. Miller is a highly trained, passionate physician-scientist uniquely poised to make an impact on
treatment for glioma. She is an Instructor of Neurology at Harvard Medical School in the Pappas Center for
Neuro-Oncology at Massachusetts General Hospital. This K08 application is designed to build on previous
cancer research experience to develop expertise in studying glioma biology. Her mentors, Drs. Cahill and
Wakimoto, are leaders in the field of IDH mutant glioma metabolism and modeling. The proposed project will
also utilize collaborations with established leaders in single-cell transcriptomics and metabolism. This expertise
is complemented by the candidate’s scientific advisors, Dr. Brastianos and Dr. Batchelor, who are experts in
translational Neuro-Oncology. This award will be further supported by the unparalleled institutional support and
environment offered by Massachusetts General Hospital and Harvard Medical School. Dr. Miller’s future goal is
to use the expertise gained during this award to study the effect of novel therapeutics in human patients with
glioma. The K08 is an important stepping stone for building a translational research program in Neuro-Oncology
and ultimately becoming an independent, R01-funded investigator.
项目总结
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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Julie JoAnn Miller其他文献
Julie JoAnn Miller的其他文献
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{{ truncateString('Julie JoAnn Miller', 18)}}的其他基金
Investigation of Sirt1 activation to target IDH mutant glioma
Sirt1 激活针对 IDH 突变神经胶质瘤的研究
- 批准号:
10456191 - 财政年份:2021
- 资助金额:
$ 19.73万 - 项目类别:
Investigation of Sirt1 activation to target IDH mutant glioma
Sirt1 激活针对 IDH 突变神经胶质瘤的研究
- 批准号:
10667496 - 财政年份:2021
- 资助金额:
$ 19.73万 - 项目类别:
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