Hydrogen sulfide functions as a tumor suppressor in glioblastoma
Hydrogen sulfide functions as a tumor suppressor in glioblastoma
批准号:
10656703
负责人:
CHRISTOPHER Michael HINE
金额:
$51.51万
依托单位国家:
美国
项目类别:
财政年份:
2023
资助国家:
美国
项目状态:
未结题
起止时间:
2023-04-01 至 2028-02-29
关键词:
AccelerationAdultAffectAgeAgingAttenuatedBiological AvailabilityBrainCell MaintenanceCell ProliferationCellsChemicalsClinicalClinical TrialsCuesCysteine DesulfhydraseDataDiagnosisElderlyEnzymesEpigenetic ProcessFDA approvedGenerationsGeneticGenetically Engineered MouseGlioblastomaGoalsGrowthHumanHydrogen SulfideHypothyroidismImmunologic SurveillanceImmunosuppressionImmunotherapyIn VitroInterventionKnock-outKnockout MiceLifeLongevityMaintenanceMalignant - descriptorMalignant neoplasm of brainMediatingMetabolicMetabolismMethimazoleMitochondriaModelingMolecularNerve DegenerationOutcomeOxidation-ReductionPatientsPharmaceutical PreparationsPre-Clinical ModelPrimary Brain NeoplasmsProductionProgression-Free SurvivalsProliferatingPropylthiouracilProtein SProteinsPublishingRadioRecurrenceRegulationRepressionResistanceRoleSamplingSignal TransductionSiteSpecimenSulfur Amino AcidsTamoxifenTestingTherapeuticTherapeutic EffectTherapeutic StudiesThyroid GlandThyroid HormonesTimeTissuesTumor BurdenTumor SuppressionTumor Suppressor ProteinsVisitage effectagedamino acid metabolismcancer stem cellclinically relevantdetection assaydietaryexperimental studyhormonal signalshuman old age (65+)immune activationimmune functionimprovedin vivojuvenile animalmetabolic fitnessmouse modelmultimodalityneoplastic cellneuralnoveloverexpressionpatient derived xenograft modelpharmacologicpre-clinicalpreventprogramsresponseself-renewalstandard of carestem cell populationstem cell self renewalstem cell survivalsulfhydrationsynergismtemozolomidetherapy resistanttreatment strategytumortumor growthtumor initiationtumor microenvironmenttumorigenic
中文摘要
摘要:胶质母细胞瘤(GBM)是成人最常见的原发性恶性脑肿瘤。“绿带运动”增长
英文摘要
ABSTRACT: Glioblastoma (GBM) is the most common malignant primary brain tumor in adults. GBM growth
and therapeutic resistance are driven by a combination of self-renewing cancer stem cells (CSCs) and an aging-
induced tumor-supportive microenvironment. CSCs are regulated by cell intrinsic genetic and epigenetic
networks, extrinsic cellular interactions with the surrounding microenvironment, and the interaction between
those intrinsic and extrinsic regulatory programs. While multiple molecular mechanisms that drive self-renewal
have been identified, the effects of advanced age on CSC maintenance has yet to be explored. Specifically, it is
unclear how advanced age alters CSC maintenance and GBM growth. A recently recognized hallmark of
advanced age is the shift in sulfur amino acid metabolism that suppresses enzyme-dependent hydrogen sulfide
(H2S) generation, signaling, and bioavailability. H2S is a redox-active metabolite that signals through protein S-
sulfhydration (R-SSnH) and impacts metabolism, immune activation, and longevity. Its enzymatic production by
cystathionine γ-lyase (CGL) is repressed by thyroid hormone (TH). H2S has both pro- and anti-tumorigenic
functions that are tumor-type dependent. However, there is limited information on cell intrinsic and tumor
microenvironment functions of H2S in GBM. Recently, we modulated H2S levels through dietary and
pharmacological interventions and found that H2S functions as a tumor suppressor in GBM and attenuates CSC
self-renewal and tumor growth in pre-clinical models. H2S generation and sulfhydration were decreased in human
GBM specimens as compared to non-tumor controls. While the data support the hypothesis that H2S functions
as a tumor suppressor in GBM, the effects of aging-induced H2S declines on GBM progression and CSCs, and
how to reverse this for clinical use, are unexplored. Based on our published findings and new preliminary data,
we hypothesize that decreased H2S production during aging promotes CSC initiation, immune
suppression, and drives GBM growth but can ultimately be reversed by anti-TH based H2S boosting
approaches. We will test this hypothesis through the following aims by integrating our newly developed H2S and
sulfhydration detection assays in combination with in vitro and in vivo GBM models that manipulate H2S
production via genetic and pharmacological interventions with human samples to provide clinical relevance. Aim
1 tests the hypothesis that aging-induced suppression of CGL-derived H2S accelerates GBM progression. Aim
2 tests the hypothesis that chemically-induced hypothyroidism stimulates CGL to increase systemic and neural
H2S production resulting in reduced GBM progression, CSC enrichment, and improved survival in preclinical
GBM models. The long-term goal of this project is to interrogate the function of H2S as a GBM tumor suppressor
that is lost during aging, while also studying the therapeutic effects of hypothyroid-induced H2S production and
signaling to reduce CSC maintenance and immune suppression. Leveraging this axis represents a new strategy
for the management of GBM that may synergize with standard of care chemo-, radio-, and immunotherapies.
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会议论文
Iron Catalyzed H2S and its Prevalence in Hemolytic and Iron Overload Disorders
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批准号:10191027
-
项目类别:
-
资助金额:$32.2万
-
财政年份:2019
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负责人:CHRISTOPHER Michael HINE
-
依托单位:
Requirement of hydrogen sulfide for the benefits of dietary sulfur amino acid restriction
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批准号:8950536
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项目类别:
-
资助金额:$12.84万
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财政年份:2015
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负责人:CHRISTOPHER Michael HINE
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依托单位:
海外基金