Oxidant Mediated Diaphragm Dysfunction in Diabetes
糖尿病中氧化剂介导的膈肌功能障碍
基本信息
- 批准号:7382503
- 负责人:
- 金额:$ 35.56万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2006
- 资助国家:美国
- 起止时间:2006-04-01 至 2010-03-31
- 项目状态:已结题
- 来源:
- 关键词:4-ethoxymethylene-2-phenyl-2-oxazoline-5-oneAblationAdmission activityAngiotensin IIAnimal ModelAnimalsBiochemicalBiological AssayCalpainCaringCell Culture TechniquesCell surfaceCellsCessation of lifeChemicalsComplementConditionContractile ProteinsCoronary ArteriosclerosisCoronary Artery BypassCritical IllnessDataDatabasesDevelopmentDiabetes MellitusDiseaseElectron TransportEndothelin-1Environmental air flowFiberFree Radical ScavengersFree RadicalsFrequenciesFunctional disorderGelGenerationsGenetic TechniquesGlucoseGoalsHandHealthHospitalizationHospitalsHyperglycemiaIn SituIn VitroIncidenceInjection of therapeutic agentInterleukinsKetonesKidney DiseasesKnock-outLinkLipid PeroxidationMeasuresMechanical ventilationMediatingMedicalMedicareMembraneMitochondriaMorbidity - disease rateMusMuscleMuscle FibersMuscle WeaknessMuscle functionNADPNADPH OxidaseNeuropathyNitric Oxide SynthaseNumbersOperative Surgical ProceduresOxidantsOxygen ConsumptionPathogenesisPathway interactionsPatientsPerformancePhosphorylationPhysiologicalPostoperative PeriodPrincipal InvestigatorProcessProductionProtein OverexpressionProtein SubunitsProteinsProteomicsPumpPurposeRateRattusResearchResearch DesignResearch PersonnelRespiratory DiaphragmRespiratory FailureRespiratory MusclesRespiratory SystemRespiratory Tract InfectionsRespiratory physiologyRetinal DiseasesReview LiteratureRiskRoleSeriesSignal TransductionSkeletal MuscleSkinSourceStreptozocinStructureSuperoxide DismutaseSuperoxidesTechniquesTestingTransgenic AnimalsTransgenic OrganismsUp-RegulationWeaningWestern BlottingWorkWorkloadXanthine Oxidasecalpastatinchemical geneticsdiabetichospital admission ratehuman AKAP13 proteinimprovedinhibitor/antagonistmitochondrial dysfunctionmortalitynon-diabeticnovel therapeuticsoxidationpreventprogramsprotein functionprotein structure functionresearch studyrespiratoryresponsetheoriestherapeutic target
项目摘要
Recent studies indicate that diabetes is associated with an increased incidence of respiratory failure, a
heightened risk of postoperative respiratory complications, and a greater need for prolonged mechanical
ventilation. However, it is not known how diabetes produces these problems. One potential explanation is
that uncontrolled diabetes alters respiratory muscle function, reducing the capacity of the respiratory pump.
The purpose of the present proposal is to examine this issue. Our central hypothesis is that poorly controlled
diabetes induces severe free radical mediated diaphragm dysfunction. We will test this hypothesis in the
following groups of studies. Aim I studies will characterize the effects of uncontrolled diabetes on diaphragm
specific force generation, changes in muscle mass, and diaphragm endurance, testing the hypothesis
diabetes induced alterations in diaphragm performance are related to increases in free radical generation.
Aim II studies will interrogate a number of free radical generating pathways in muscle (including the cell
surface NADPH oxidase) and determine which pathways are responsible for increased free radical
generation in the diaphragm in diabetes. Aim III studies will determine if iNOS is upregulated in the
diaphragm in diabetes, and will test the hypothesis that iNOS acts as an upstream modulator of free radical
generation. Aim IV studies will examine several downstream targets of diabetes induced free radical
generation in the diaphragm that are responsible for reductions in diaphragm performance, including
contractile protein alterations, calpain mediated reductions in muscle mass, and alterations in mitochondrial
ATP generating capacity. A variety of physiologic, biochemical, proteomic, fluorogenic, pharmacologic and
genetic techniques will be used to test these hypotheses. Our preliminary data represent the first
demonstration of upregulation of NADPH oxidase subunit proteins in skeletal muscle in any disease process,
and suggest that iNOS regulates NADPH oxidase activity and free radical generation in the diaphragm in
diabetes. These new data should provide important information regarding the pathogenesis of diabetes
induced diaphragm dysfunction, and uncover pathways which could provide novel therapeutic targets for
treatment of respiratory muscle weakness in this condition.
最近的研究表明,糖尿病与呼吸衰竭的发生率增加有关
术后呼吸并发症的风险增加,并更需要长时间的机械
通风。但是,尚不知道糖尿病如何产生这些问题。一个潜在的解释是
不受控制的糖尿病会改变呼吸肌功能,从而降低呼吸泵的能力。
本提案的目的是研究这个问题。我们的中心假设是控制不善
糖尿病会诱导严重的自由基介导的隔膜功能障碍。我们将在
以下研究组。目的I研究将表征不受控制的糖尿病对膜片的影响
特定的力产生,肌肉质量的变化和diaphragm耐力,检验假设
糖尿病诱导的隔膜性能改变与自由基产生的增加有关。
AIM II研究将询问肌肉中的许多自由基产生途径(包括细胞
表面NADPH氧化酶)并确定哪些途径负责增加自由基
糖尿病的膜片产生。 AIM III研究将确定INOS是否在
糖尿病中的隔膜,并将检验以下假设:iNOS充当自由基的上游调节剂
一代。 AIM IV研究将检查糖尿病引起的自由基的几个下游靶标
隔膜的产生,负责降低隔膜性能的作用,包括
收缩蛋白改变,钙蛋白酶介导的肌肉质量减少以及线粒体的改变
ATP产生能力。多种生理学,生化,蛋白质组学,荧光,药理学和
遗传技术将用于检验这些假设。我们的初步数据代表第一个
证明在任何疾病过程中骨骼肌中NADPH氧化酶亚基蛋白上调的上调,
并提示iNOS调节diaphragm中的NADPH氧化酶活性和自由基产生
糖尿病。这些新数据应提供有关糖尿病发病机理的重要信息
诱导的diaphragm功能障碍,并发现可以提供新的治疗靶标的途径
在这种情况下治疗呼吸道肌肉无力。
项目成果
期刊论文数量(0)
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{{ truncateString('LEIGH A CALLAHAN', 18)}}的其他基金
Mitochondrially Targeted Therapies for Sepsis Induced Diaphragm Dysfunction
线粒体靶向治疗脓毒症引起的膈肌功能障碍
- 批准号:
10175004 - 财政年份:2018
- 资助金额:
$ 35.56万 - 项目类别:
Effects of Sleep Deprivation on Infection Induced Organ Failure
睡眠不足对感染引起的器官衰竭的影响
- 批准号:
8438584 - 财政年份:2013
- 资助金额:
$ 35.56万 - 项目类别:
Effects of Sleep Deprivation on Infection Induced Organ Failure
睡眠不足对感染引起的器官衰竭的影响
- 批准号:
8793804 - 财政年份:2013
- 资助金额:
$ 35.56万 - 项目类别:
Effects of Sleep Deprivation on Infection Induced Organ Failure
睡眠不足对感染引起的器官衰竭的影响
- 批准号:
8620709 - 财政年份:2013
- 资助金额:
$ 35.56万 - 项目类别:
Oxidant Mediated Diaphragm Dysfunction in Diabetes
糖尿病中氧化剂介导的膈肌功能障碍
- 批准号:
7210745 - 财政年份:2006
- 资助金额:
$ 35.56万 - 项目类别:
Oxidant Mediated Diaphragm Dysfunction in Diabetes
糖尿病中氧化剂介导的膈肌功能障碍
- 批准号:
7582346 - 财政年份:2006
- 资助金额:
$ 35.56万 - 项目类别:
Oxidant Mediated Diaphragm Dysfunction in Diabetes
糖尿病中氧化剂介导的膈肌功能障碍
- 批准号:
7102098 - 财政年份:2006
- 资助金额:
$ 35.56万 - 项目类别:
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