CRITICAL TARGETS IN HYPEROXIC MITOCHONDRIAL INJURY
高氧线粒体损伤的关键目标
基本信息
- 批准号:7716163
- 负责人:
- 金额:$ 2.26万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2008
- 资助国家:美国
- 起止时间:2008-05-01 至 2009-04-30
- 项目状态:已结题
- 来源:
- 关键词:Aconitate HydrataseAdenine NucleotidesAdultAntioxidantsBindingBiochemicalBiological AssayBronchopulmonary DysplasiaCell RespirationChronic lung diseaseComplexComputer Retrieval of Information on Scientific Projects DatabaseContinuous InfusionElectron MicroscopyEnvironmental air flowEnzymesExposure toFundingGlutamineGlutathioneGlycolysisGrantHistopathologyHyperoxiaInjuryInstitutionLungMeasuresMitochondriaModelingNewborn InfantOxidantsOxidative StressOxygenPapioPremature BirthProteinsRateRattusResearchResearch PersonnelResourcesRespiratory distressS-AdenosylmethionineSourceStressSulfur Amino AcidsSuperoxide DismutaseSupplementationTXN geneTestingThioredoxinTranscriptional ActivationUnited States National Institutes of HealthUp-RegulationVoltage-Dependent Anion Channelbasehexokinaseporin
项目摘要
This subproject is one of many research subprojects utilizing the
resources provided by a Center grant funded by NIH/NCRR. The subproject and
investigator (PI) may have received primary funding from another NIH source,
and thus could be represented in other CRISP entries. The institution listed is
for the Center, which is not necessarily the institution for the investigator.
Bronchopulmonary dysplasia (BPD) is a common, disabling and sometimes fatal chronic lung disease. It frequently accompanies premature birth and treatment of respiratory distress with artificial ventilation and high concentrations of inspired oxygen (hyperoxia). The biochemical basis of BPD is not well understood. In the baboon, exposure to hyperoxia is required treatment in both the ultra-premature (125 d) and premature (140) model of BPD. Hyperoxia damages mitochondria results in loss of aconitase activity, decreased mitochondrial and cell respiration, and loss of ATP. On that basis, this proposal's principal hypothesis is that adaptation to hyperoxic stress requires up-regulation of glycolytic, and/or glutaminolytic, enzymes. Because hexokinase rate- limits glycolysis in lung, it is hypothesized that expression of lung hexokinase(s) is up-regulated. Replacement of deficient mitochondrial anti-oxidants may alleviate early respiratory distress and resulting BPD and decrease up regulation of glycolytic enzymes. These hypotheses will be tested in these AIMS; 1) Determine differential expression of mRNA's encoding components of the mitochondrial porin complex-hexokinases (HKs), porins, and adenine nucleotide translocators (ANT), these same proteins, and relevant glycolytic and glutaminolytic enzymes; 2) Define early status of critical anti-oxidants (glutathione [GSH], thioredoxin [TRX], superoxide dismutases]), their precursors (S-adenosylmethionine), and oxidant target (aconitase) markers, and (3) Define the efficacy of early, continuous infusion of S-adenosylmethionine (AdoMet), a precursor of cellular and mitochondrial glutathione (GSH), on these markers and pulmonary histopathology of BPD. Hexokinase binding to, or release from, mitochondria will be quantitied using immunogold electron microscopy. Activities of HK, phosphofructokinase, and additional critical glycolytic and glutaminolytic enzymes also will be assayed. Lung GSH, TRX, and AdoMet, as well as circulating GSH, AdoMet, and sulfur amino acids will be measured early in the 125 d model. Together, these approaches will help define whether changes in hexokinase activity expression, known to occur in lungs of adult rats made oxygen-tolerant, also occur in the premature newborn baboon. In addition, they will indicate whether or not increased expression of pulmonary glutamine- utilizing enzymes also occurs during pulmonary oxidative stress and whether anti-oxidant stress and whether anti-oxidant supplementation modifies these adaptations.
这个子项目是许多研究子项目中的一个
由NIH/NCRR资助的中心赠款提供的资源。子项目和
研究者(PI)可能从另一个NIH来源获得了主要资金,
因此可以在其他CRISP条目中表示。所列机构为
研究中心,而研究中心不一定是研究者所在的机构。
支气管肺发育不良(BPD)是一种常见的,致残的,有时是致命的慢性肺部疾病。它经常伴随早产和呼吸窘迫的人工通气和高浓度吸入氧(高氧)治疗。BPD的生物化学基础还不清楚。在狒狒中,在超早产(125天)和早产(140天)BPD模型中均需要暴露于高氧治疗。高氧损伤线粒体导致乌头酸酶活性丧失、线粒体和细胞呼吸降低以及ATP丧失。在此基础上,该提议的主要假设是,适应高氧应激需要上调糖酵解和/或氨基葡萄糖分解酶。由于己糖激酶速率限制肺中的糖酵解,因此假设肺己糖激酶的表达上调。补充线粒体抗氧化剂可以减轻早期呼吸窘迫和BPD,减少糖酵解酶的上调。1)确定线粒体孔蛋白复合物-己糖激酶(HK)、孔蛋白和腺嘌呤核苷酸移位器(ANT)、这些相同的蛋白质以及相关的糖酵解和精氨酸分解酶的mRNA编码组分的差异表达; 2)确定关键抗氧化剂的早期状态(谷胱甘肽[GSH],硫氧还蛋白[TRX],超氧化物歧化酶]),其前体(S-腺苷甲硫氨酸)和氧化剂靶标(顺乌头酸酶)标记物,和(3)确定早期连续输注S-腺苷甲硫氨酸(AdoMet)(细胞和线粒体谷胱甘肽(GSH)的前体)的功效,这些标志物和BPD的肺组织病理学。将使用免疫金电子显微镜定量己糖激酶与线粒体的结合或从线粒体释放。还将测定HK、磷酸果糖激酶和其他关键糖酵解酶和精氨酸分解酶的活性。将在125天模型的早期测量肺GSH、TRX和蛋氨酸,以及循环GSH、蛋氨酸和含硫氨基酸。总之,这些方法将有助于确定是否在己糖激酶活性表达的变化,已知发生在肺的成年大鼠制成耐氧,也发生在早产新生狒狒。此外,它们将表明肺谷氨酰胺利用酶的表达增加是否也发生在肺氧化应激期间,以及抗氧化应激和抗氧化剂补充剂是否改变这些适应。
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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Carl W White其他文献
CXCL17 induces activation of human mast cells via MRGPRX2
CXCL17 通过 MRGPRX2 诱导人类肥大细胞激活
- DOI:
- 发表时间:
2024 - 期刊:
- 影响因子:0
- 作者:
Jie Ding;Christina Hillig;Carl W White;Nithya A Fernandopulle;Holly Anderton;Johannes S Kern;Michael P. Menden;Graham A Mackay - 通讯作者:
Graham A Mackay
3 ROS : reactive oxygen species RT-qPCR : reverse transcription quantitative PCR SM : sulfur mustard SpO 2 : peripheral oxygen saturation tPA : tissue plasminogen activator
3 ROS : 活性氧 RT-qPCR : 逆转录定量 PCR SM : 硫芥 SpO 2 : 外周血氧饱和度 tPA : 组织纤溶酶原激活剂
- DOI:
- 发表时间:
2023 - 期刊:
- 影响因子:0
- 作者:
Heidi J. Nick;Carly A Johnson;Amber R. Stewart;Sarah Christeson;A. Leslie;Bloomquist;Amanda S. Appel;A. Donkor;L. Veress;B. Logue;E. Preston;Bratcher;Carl W White - 通讯作者:
Carl W White
Carl W White的其他文献
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{{ truncateString('Carl W White', 18)}}的其他基金
New Developments in Chemical Countermeasures: CounterACT 2018
化学对抗新进展:CounterACT 2018
- 批准号:
9490163 - 财政年份:2016
- 资助金额:
$ 2.26万 - 项目类别:
Hypoxic-Inducible Factors in Neonatal Pulmonary Hypertension
新生儿肺动脉高压的缺氧诱发因素
- 批准号:
8214146 - 财政年份:2011
- 资助金额:
$ 2.26万 - 项目类别:
Novel antioxidant therapeutics for sulfur mustard toxicity (U54)
针对硫芥毒性的新型抗氧化疗法 (U54)
- 批准号:
7294907 - 财政年份:2006
- 资助金额:
$ 2.26万 - 项目类别:
Novel therapeutics for vesicants and toxic inhaled chemicals (U54)
针对出疱剂和有毒吸入化学品的新型疗法 (U54)
- 批准号:
8737370 - 财政年份:2006
- 资助金额:
$ 2.26万 - 项目类别:
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