BLR&D Research Career Scientist Award Application
BLR
基本信息
- 批准号:10265408
- 负责人:
- 金额:--
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2018
- 资助国家:美国
- 起止时间:2018-04-01 至 2025-03-31
- 项目状态:未结题
- 来源:
- 关键词:Alzheimer&aposs DiseaseAmino AcidsApoptosisArchitectureAreaAwardBacterial ModelBindingBinding ProteinsBiochemicalBiochemistryBioenergeticsBrain InjuriesCardiacCellsClinicalCoenzyme Q10ComplexDNADevelopmentDiabetes MellitusDiagnosisDiseaseEarly DiagnosisEnzymesEpigenetic ProcessEthicsFamilyFumaratesFunctional disorderGene ExpressionGenerationsGenesGenetic PolymorphismGenetic TranscriptionHealthHeart DiseasesHemeHomeostasisHumanHuman bodyHypoxia Inducible FactorInflammationInflammatoryInflammatory ResponseInjuryInvestigationIschemiaKidney DiseasesLaboratoriesLaboratory StudyLeadLipidsMaintenanceMalignant NeoplasmsMalonatesMembraneMethodsMineralsMitochondriaMitochondrial ProteinsModelingMultienzyme ComplexesMultiple SclerosisMuscle WeaknessMutationMyocardial InfarctionNADHNADH dehydrogenase (ubiquinone)Nerve DegenerationNerve RegenerationNeurodegenerative DisordersNobel PrizeOrganellesOxidation-ReductionOxidative PhosphorylationOxidesPaperParkinson DiseasePathway interactionsPatientsPermeabilityPharmaceutical PreparationsPhilosophyPhysiologyPlayPoint MutationPoisonProcessProcollagen-Proline DioxygenaseProtein RegionProtonsPsoriasisPublishingQuinone ReductasesReactive Oxygen SpeciesRegulatory ElementRelapseReperfusion TherapyResearchResolutionRespirationRespiratory ChainRoentgen RaysRoleScienceScientistSeriesSeveritiesSignal TransductionSignaling MoleculeStressStrokeStructureStudy modelsSuccinate DehydrogenaseSuccinatesSystemTherapeuticTherapeutic UsesThree-dimensional analysisTimeTraumatic Brain InjuryUbiquinoneUnited States National Academy of SciencesVascular remodelingVeteransVitaminsWorkcareercofactordesignhealinghistone demethylasein vivoinhibitor/antagonistinsightmembermethod developmentmitochondrial dysfunctionmitochondrial membranemitochondrial metabolismmouse modelnewsnuclear factor-erythroid 2nucleotide metabolismpatient populationpreventprogramsprotein complexprotein metabolismprotein structureprotein structure functionresearch and developmentrespiratoryresponsesmall molecule inhibitorsuccessthree dimensional structuretumor
项目摘要
Our laboratory is focused on understanding how mitochondrial function contributes to health and
disease. As the major energy generating organelle of the cell dysfunction of mitochondria has been
implicated in debilitating diseases prevalent in the VA patient population. These include, neurodegenerative
diseases (Parkinson's, Alzheimer's), diabetes, cancer, and heart disease. Altered mitochondrial
metabolism can result in changed levels of tricarboxylic (TCA) cycle metabolites, (such as succinate or
fumarate), that act as signaling molecules to promote a pro-inflammatory state. This can lead to changes in
gene transcription, through the induction of reactive oxygen species (ROS), stabilization of hypoxia-
inducible factor-1α (HIF-1α), or the nuclear factor erythroid-2-related factor-2 (Nrf2) transcription pathway
that responds to pro-inflammatory stress. Our laboratory investigates the structure and function of two
essential members of the mitochondrial respiratory chain both of which reduce ubiquinone (CoQ10) used by
the oxidative phosphorylation system to generate energy. We study the function of Complex I
(NADH:ubiquinone oxidoreductase) which is the largest membrane-bound component of the mitochondrion.
NADH generated by the TCA cycle is used by Complex I to reduce CoQ10 and this activity controls the
NADH/NAD+ ratio. The enzyme is regulated by a structural change near the membrane domain termed the
Active/De-Active (A/D) transition, which we first showed occurred in vivo. We also study succinate
dehydrogenase (SDH/Complex II) which is a membrane-bound heterotetramer of dual function. SDH
oxidizes succinate to fumarate in the TCA cycle while reducing CoQ10 for energy generation. Malfunction of
SDH results in accumulation of succinate in the cell which promotes inflammation. It has been shown that
inhibitors of SDH can have a positive effect in treating damage form ischemia/reperfusion in both stroke and
cardiac models. Our studies of SDH have shown how the reversible inhibitor malonate binds to the enzyme
and causes inhibition. We are now focused on understanding how we can regulate the activity and
structure of both Complexes I & II so that this information can be used to treat disease.
One model we will use is to investigate how TCA cycle metabolites can be used to treat traumatic
brain injury (TBI) or stroke. Dimethyl fumarate (DMF) is an approved drug for treating relapsing multiple
sclerosis and psoriasis and Dimethyl malonate (DMM) is a cell-permeable non-toxic compound which in
vivo can be used to inhibit SDH. We hypothesize that in the brain injury model that DMM will block
succinate accumulation following injury and prevent the signaling that produces ROS during
ischemia/reperfusion; thus, reducing inflammation, the severity of the injury, and enhance healing. We use
mouse models for these studies. We will also determine if the epigenetic modifier DMF can reduce the
inflammation caused by TBI thus lessening the severity of the injury and enhance neuro-regeneration.
We were the first to determine the x-ray structure of SDH and have provided major insight into its
catalytic mechanism and function. How the enzyme complex is assembled, however, remains and area of
intense investigation. We are now studying the assembly of human Complex II using known human
assembly factors, needed for incorporation of redox cofactors necessary for function of the enzyme. It has
been shown that when assembly is compromised this can lead to tumor formation in humans. We have had
success expressing and analyzing the three-dimensional structure of the human structural subunits of SDH
expressed in bacterial models. Thus, for the first time the structure of these assembly intermediates will be
known. This information is needed to develop small molecule inhibitors/activators that can be used for
treatment of diseases associated with mitochondrial dysfunction and control metabolite levels in cells.
我们实验室的重点是了解线粒体功能对健康和
项目成果
期刊论文数量(0)
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科研奖励数量(0)
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Gary Cecchini其他文献
Gary Cecchini的其他文献
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{{ truncateString('Gary Cecchini', 18)}}的其他基金
Regulation of NADH: ubiquinone oxidoreductase (complex *
NADH 的调节:泛醌氧化还原酶(复合物 *
- 批准号:
6548756 - 财政年份:2002
- 资助金额:
-- - 项目类别:
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