Akt-mediated phosphorylation of hsp70 regulates mitochondrial localization of SOD2 and oxidative stress in pulmonary artery endothelial cells during postnatal transition
Akt 介导的 hsp70 磷酸化调节出生后过渡期间肺动脉内皮细胞中 SOD2 的线粒体定位和氧化应激
基本信息
- 批准号:9162675
- 负责人:
- 金额:$ 15.61万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2016
- 资助国家:美国
- 起止时间:2016-09-01 至 2021-07-31
- 项目状态:已结题
- 来源:
- 关键词:ATP phosphohydrolaseAdvisory CommitteesAffectAnionsAntioxidantsBindingBiochemistryBiological AssayBiological AvailabilityBiologyBirthBlood VesselsCardiopulmonaryCell Culture TechniquesCellsCessation of lifeClinicalCytosolDataDevelopment PlansDevelopmental BiologyDiseaseEndotheliumEnvironmentEnzymesExposure toFailureFamilyFetal LungFree RadicalsFutureGeneticGoalsGrowthHeat-Shock ResponseIn VitroInfantInfant HealthKineticsKnock-outKnowledgeLeadLearning SkillLive BirthLungMeasuresMediatingMedicalMentorsMentorshipMitochondriaModelingMolecularMolecular ChaperonesMusNADPH OxidaseNOS3 geneNeonatalNeonatal Intensive Care UnitsNeonatologyNeurodevelopmental ImpairmentNewborn InfantNitric OxideOutcomeOxidation-ReductionOxidative PhosphorylationOxidative StressOxygenOxygen ConsumptionPathogenesisPathway interactionsPatientsPerinatalPersistent Fetal Circulation SyndromePhosphorylationPhosphorylation SitePlayPositioning AttributePost-Translational Protein ProcessingPremature InfantProductionProtein DephosphorylationProteinsProto-Oncogene Proteins c-aktPublic HealthPulmonary Vascular ResistancePulmonary artery structureReactive Oxygen SpeciesRegulationResearchResearch PersonnelRespirationRespiratory FailureRiskRoleSOD2 geneSignal PathwaySignal TransductionSourceSuperoxide DismutaseSuperoxidesTestingTrainingTraining ProgramsTranscriptional RegulationTransgenic MiceUnited StatesVasodilationWisconsinWorkbasecareer developmentclinical careexperiencefetalfetus hypoxiahealth economicsimprovedimproved outcomein uteroin vivoinhibitor/antagonistmedical schoolsmembernew therapeutic targetnovelnovel therapeuticspostnatalprotein protein interactionpulmonary artery endothelial cellresponseskillstherapeutic targettreatment strategyubiquitin ligase
项目摘要
ABSTRACT
My goal is to become an independent investigator in disease-oriented research in the newborn with a specific
focus on the regulation of mitochondrial oxidative stress in persistent pulmonary hypertension of the newborn
(PPHN). PPHN affects 2-6/1000 live births and is a common cause of cardiopulmonary failure in the newborn.
Of these infants, >30% fail medical treatment and need invasive support measures (ECMO). Oxidative stress
is strongly implicated in the pathogenesis of PPHN. NADPH oxidases are considered the primary source of
superoxide (O2¯) in the pulmonary endothelium. Mitochondrial oxygen consumption during respiration produc-
es influx of O2¯ in the mitochondria as a byproduct of oxidative phosphorylation. Recent evidence indicates
that reactive oxygen species (ROS) produced by mitochondria induce the activation of NADPH oxidases, lead-
ing to ROS induced ROS formation. However, the regulation of mitochondrial O2¯formation remains unknown.
Identification of the adaptive mechanisms that minimizes mitochondrial O2¯formation during exposure to oxy-
gen at birth may identify additional therapeutic targets in PPHN. I will begin to achieve this goal by engaging in
a Career Development plan that logically allows me to expand my prior skills and build new skills in mouse ge-
netics, analysis of protein-protein interactions and identification of novel signaling pathways pertinent to endo-
thelial biology. This plan integrates didactic training in genetics, biochemistry and free radical biology with
learning of skills from my Mentors and Scientific Advisory Committee at the Medical College of Wisconsin who
combined have expertise in endothelial biology, developmental vascular biology, free radical and mitochondrial
biology. The Mentorship and Career Development plan are integrated with the proposed research objectives to
test the hypothesis that Akt induces a post translational modification of hsp70 and modulates the interactions
of hsp70 with two recently identified proteins namely: an Obg like ATPase-1 (OLA1) that facilitates SOD2 im-
port, and CHIP, which is a chaperone-associated ubiquitin ligase that targets hsp70 for degradation. Phos-
phorylation of hsp70 by Akt promotes the interaction of hsp70 with OLA1 and facilitates the mitochondrial im-
port of SOD2 to reduce free O2¯during postnatal transition. The first aim seeks to determine the contributions
of OLA1 and CHIP to the regulation of mitochondrial redox signaling in PAECs. We will use transgenic mice, in
vitro kinetic assays and cell culture to determine the contributions of OLA1 and CHIP to mitochondrial redox
signaling in PAECs and identify how OLA1 and CHIP mechanistically regulate mitochondrial SOD2 import and
ROS production. The second aim will determine the mechanistic role of PI3K/Akt signaling pathway in regulat-
ing the mitochondrial import of SOD2 and the functional relevance of this mechanism to postnatal adaptation.
The successful completion of the proposed studies and training program will lead to future studies investigating
preventable and treatment strategies to improve outcomes in PPHN patients, with the goal of reducing the
economic and health burden due to PPHN.
摘要
项目成果
期刊论文数量(0)
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科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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{{ truncateString('Adeleye J afolayan', 18)}}的其他基金
Akt-mediated phosphorylation of hsp70 regulates mitochondrial localization of SOD2 and oxidative stress in pulmonary artery endothelial cells during postnatal transition
Akt 介导的 hsp70 磷酸化调节出生后过渡期间肺动脉内皮细胞中 SOD2 的线粒体定位和氧化应激
- 批准号:
10402122 - 财政年份:2016
- 资助金额:
$ 15.61万 - 项目类别:
Akt-mediated phosphorylation of hsp70 regulates mitochondrial localization of SOD2 and oxidative stress in pulmonary artery endothelial cells during postnatal transition
Akt 介导的 hsp70 磷酸化调节出生后过渡期间肺动脉内皮细胞中 SOD2 的线粒体定位和氧化应激
- 批准号:
9981796 - 财政年份:2016
- 资助金额:
$ 15.61万 - 项目类别:
Akt-mediated phosphorylation of hsp70 regulates mitochondrial localization of SOD2 and oxidative stress in pulmonary artery endothelial cells during postnatal transition
Akt 介导的 hsp70 磷酸化调节出生后过渡期间肺动脉内皮细胞中 SOD2 的线粒体定位和氧化应激
- 批准号:
9750015 - 财政年份:2016
- 资助金额:
$ 15.61万 - 项目类别:
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