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HIF-Mediated Detrimental Consequences of Chronic Intermittent Hypoxia

HIF-Mediated Detrimental Consequences of Chronic Intermittent Hypoxia
HIF 介导的慢性间歇性缺氧的有害后果
批准号:
9243108
负责人:
JOSEF T PRCHAL
金额:
$0.0万
依托单位国家:
美国
项目类别:
财政年份:
2017
资助国家:
美国
项目状态:
已结题
起止时间:
2017-01-01 至 2020-12-31
关键词:
AdultAffectApneaAttenuatedB-LymphocytesBNIP3L geneBloodBlood CellsBlood PlateletsBlood PressureBlood VesselsBreathingCarbon MonoxideCarotid BodyCellsChicagoChronicClinicalCollaborationsContinuous Positive Airway PressureCystathionineDataDiabetes MellitusDiffuseDiseaseDown-RegulationEmergency department visitEpidemicErythrocytesErythroidErythropoiesisErythropoietinExcisionExhalationFrequenciesFunctional disorderGenerationsGenesGlucose IntoleranceGoalsHealthHealthcare SystemsHematocrit procedureHemolysisHormonesHospitalizationHydrogen SulfideHypertensionHypoxemiaHypoxiaHypoxia Inducible FactorImpaired cognitionInflammationLeadLinkLungLyaseMalignant NeoplasmsMeasuresMediatingMedicalMedicineMemoryMessenger RNAMetabolicMicroRNAsMitochondriaModelingMolecularMononuclearMorbidity - disease rateMyocardial InfarctionObesityObstructive Sleep ApneaOxygenPathway interactionsPatientsPeriodicityPersonsPharmacologyPlasmaPlayPolycythemiaPopulationProcessProductionProspective StudiesPulmonary Heart DiseasePulmonologyReactive Oxygen SpeciesRecurrenceReflex actionReflex controlRegulationResearchResearch ProposalsReticulocytesRoleSecondary toSeveritiesSleepSleep Apnea SyndromesT-LymphocyteTestingTissuesTranscriptUniversitiesUp-RegulationUtahVeteransVisitbHLH-PAS factor HLFbody sensecatalasecatalase-polyethylene glycolcostdesignfallsgranulocyteheme oxygenase-2hypoxia inducible factor 1indexinginsightmetabolomemonocytemouse modelneurotransmissionnovelpreventprofessorprogenitorpyruvate kinase deficiencysensortranscription factorurgent care

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中文摘要
翻译
阻塞性睡眠呼吸暂停(OSA),一个术语,指睡眠期间呼吸受阻或受阻, 是一种非常普遍的医学状况,随着肥胖和糖尿病而增加,并影响9-18%的成年人 美国人口阻塞性睡眠呼吸暂停的发生是由于睡眠期间反复出现的上呼吸道塌陷, 空气流动伴随着体内氧气的周期性变化,并导致慢性间歇性缺氧状态。许多 基本过程,如红细胞的产生,能量调节和新血液的形成 血管,由缺氧调节。阻塞性睡眠呼吸暂停综合症是一种非常常见的问题, 高血压糖尿病记忆力差心脏病发作缺氧导致缺氧诱导因子的上调 (HIFs)。HIF-1和HIF-2是在对促红细胞生成素(EPO)的研究中发现的, 刺激红系祖细胞并调节红细胞的产生,这是PI先前 VA支持。 该应用程序旨在获得对HIF贡献的新见解,HIF调节 红细胞生成,OSA的病理生理学。这一建议的PI一直很感兴趣,与此相反, 其他缺氧条件下,他的主要临床/学术重点红细胞增多症/红细胞增多症是不常见的 OSA的特点。在长时间缺氧期间,HIF介导红细胞生成的增加,导致红细胞生成的增加。 红细胞(RBC)质量。当恢复到常氧时,增加的RBC质量突然过度校正, 优先销毁,即,缺氧形成的年轻红细胞的溶血,这种现象被称为 新细胞溶解我们建立了一种新的小鼠新细胞溶解模型,并使用该模型表明新细胞溶解 是由活性氧(ROS)的过度积累,红细胞中线粒体的增加, 和增加的微RNA miR-21,其下调过氧化氢酶。 我们还获得了初步的数据,表明新细胞溶解是防止细胞凋亡的主要机制。 OSA患者的红细胞增多症。我们观察到OSA患者的红细胞和网织红细胞 过氧化氢酶转录物和活性降低,沿着miR-21增加,并且这些水平随着miR-21增加而正常化。 CPAP治疗。我们还观察到,在未纠正的OSA中,线粒体质量和ROS水平增加, 不仅在网织红细胞和成熟红细胞中发现,而且在其它血细胞如血小板、T细胞、B- 细胞、粒细胞和单核细胞。CPAP治疗后,线粒体ROS减少, 线粒体质量恢复正常 为了实现我们在这项研究计划中概述的研究目标,我们将阐明 使用外周血细胞证实我们的初步发现, 继发于大多数OSA患者的慢性间歇性缺氧。我们将确定代谢 在小鼠新细胞溶解模型中慢性间歇性与持续性缺氧的后果,并评估 HIF药理学操作的影响。我们将评估一氧化碳(CO)的影响, 其通过溶血增加对颈动脉体(CB)的活性。CB是动脉的关键传感器 血氧含量缺氧会增加来自CB的神经信号,通过化学感觉反射, 呼吸和血压,这是对缺氧的主要适应。增强的CB化学感觉反射发挥作用, 在OSA病理生理学中的重要作用。新出现的证据表明, 涉及血红素加氧酶-2和氢产生CO之间的血氧依赖性相互作用 由胱硫醚裂解酶合成硫化物。我们将使用呼出CO潮气末呼吸分析仪进行评估, OSA中溶血RBC产生的CO增加是否影响CB感受和随后的化学感受 反射
英文摘要
Obstructive sleep apnea (OSA), a term for periods during sleep when breathing is blocked or impeded, is a highly prevalent medical condition, increases with obesity and diabetes, and affects 9-18% of the adult U.S. population. OSA occurs because of recurrent upper airway collapse during sleep leading to reductions in airflow with cyclic changes in body oxygen, and results in a state of chronic intermittent hypoxia. Many essential processes, such as production of red blood cells, energy regulation, and formation of new blood vessels, are regulated by hypoxia. OSA is an exceedingly common problem that has been linked to high blood pressure, diabetes, poor memory and heart attacks. Hypoxia leads to up-regulation of hypoxia-inducible factors (HIFs). HIF-1 and HIF-2 were discovered as a result of studies of erythropoietin (EPO), the key hormone that stimulates erythroid progenitors and regulates the production of erythrocytes, the subject of the PI's previous VA support. This application is designed to gain novel insights into the contribution of HIFs, which regulate erythropoiesis, to the pathophysiology of OSA. The PI of this proposal has been intrigued that, in contrast to other hypoxic conditions, his major clinical/academic focus of polycythemia/erythrocytosis is not a common feature of OSA. During prolonged hypoxia, HIFs mediate an increase in erythropoiesis, leading to an increased red blood cell (RBC) mass. Upon return to normoxia, the increased RBC mass is abruptly overcorrected by the preferential destruction, i.e., hemolysis, of hypoxia-formed young RBCs, a phenomenon termed neocytolysis. We created a novel mouse model of neocytolysis and used this model to show that neocytolysis is mediated by excessive accumulation of reactive oxygen species (ROS), increased mitochondria in RBCs, and increased micro RNA miR-21 which down-regulates catalase. We also obtained preliminary data suggesting that neocytolysis is the main mechanism preventing polycythemia in patients with OSA. We observed that erythrocytes and reticulocytes of OSA patients have reduced catalase transcripts and activity, along with increased miR-21, and that these levels normalize with CPAP treatment. We also observed that in uncorrected OSA, increased mitochondrial mass and levels of ROS are found not only in reticulocytes and mature RBCs, but also in other blood cells such as platelets, T-cells, B- cells, granulocytes, and mononuclear cells. With CPAP treatment, mitochondrial ROS decrease and mitochondrial mass normalizes. To accomplish our research goals outlined in this research proposal, we will elucidate OSA changes in HIF-regulated pathways using peripheral blood cells to confirm our preliminary findings that neocytolysis occurs secondary to chronic intermittent hypoxia in most OSA patients. We will determine the metabolic consequences of chronic intermittent versus sustained hypoxia in a mouse model of neocytolysis and assess the effect(s) of pharmacological manipulation of HIFs. We will evaluate the effects of carbon monoxide (CO), which is increased by hemolysis, on the activity of the carotid body (CB). The CB is the key sensor of arterial blood oxygen. Hypoxia increases neural signals from the CB which, through chemosensory reflexes, controls breathing and blood pressure, a principal adaptation to hypoxia. Enhanced CB chemosensory reflexes play a substantial role in OSA pathophysiology. Emerging evidence suggests that hypoxic sensing by the CB involves blood oxygen-dependent interplay between CO generation by heme oxygenase-2 and hydrogen sulfide synthesis by cystathionine-ϒ-lyase. We will evaluate, using an exhaled CO end-tidal breath analyzer, whether increased CO produced by hemolyzed RBC in OSA influences CB sensing and ensuing chemosensory reflexes.
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会议论文
Mechanism of thrombosis in two myeloproliferative neoplasms (MPNs), polycythemia vera and essential thrombocythemia
HIF-Mediated Detrimental Consequences of Chronic Intermittent Hypoxia
Erythropoietin in Non-Erythroid Cells: Function and Regulation
Erythropoietin in Non-Erythroid Cells: Function and Regulation
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