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HIF-Mediated Detrimental Consequences of Chronic Intermittent Hypoxia

HIF 介导的慢性间歇性缺氧的有害后果

基本信息

批准号：
10237109
负责人：
JOSEF T PRCHAL
金额：
--
依托单位：
VA SALT LAKE CITY HEALTHCARE SYSTEM
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-01-01 至 2021-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10237109
关键词：
Adult Affect Air Movements Apnea Attenuated B-Lymphocytes BNIP3L gene Blood Blood Cells Blood Platelets Blood Pressure Blood Vessels Breathing Carbon Monoxide Carotid Body Cells Chicago Chronic Clinical Collaborations Continuous Positive Airway Pressure Cystathionine Data Diabetes Mellitus Diffuse Disease Down-Regulation Emergency department visit Epidemic Erythrocytes Erythroid Erythropoiesis Erythropoietin Excision Exhalation Frequencies Functional disorder Generations Genes Glucose Intolerance Goals Health Healthcare Systems Hematocrit procedure Hemolysis Hormones Hospitalization Hydrogen Sulfide Hypertension Hypoxemia Hypoxia Hypoxia Inducible Factor Impaired cognition Inflammation Lead Link Lung Lyase Malignant Neoplasms Measures Mediating Medical Medicine Memory Messenger RNA Metabolic MicroRNAs Mitochondria Modeling Molecular Mononuclear Morbidity - disease rate Myocardial Infarction Obesity Obstructive Sleep Apnea Oxygen Pathway interactions Patients Periodicity Persons Pharmacology Plasma Play Polycythemia Population Process Production Prospective Studies Pulmonary Heart Disease Pulmonology Reactive Oxygen Species Recurrence Reflex action Reflex control Regulation Research Research Proposals Reticulocytes Role Secondary to Severities Sleep Sleep Apnea Syndromes T-Lymphocyte Testing Tissues Transcript Universities Up-Regulation Utah Veterans Visit bHLH-PAS factor HLF body sense catalase catalase-polyethylene glycol cost design falls granulocyte heme oxygenase-2 hypoxia inducible factor 1 indexing insight metabolome monocyte mouse model neurotransmission normoxia novel prevent professor progenitor pyruvate kinase deficiency sensor thrombotic complications transcription factor urgent care

项目摘要

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.

阻塞性睡眠呼吸暂停(OSA)，是指睡眠中呼吸受阻或受阻的时期，是一种非常普遍的疾病，随着肥胖和糖尿病的增加，影响到9%-18%的成年人美国人口。OSA的发生是由于睡眠期间反复出现的上呼吸道塌陷导致睡眠时间减少体内氧气循环变化的气流，导致慢性间歇性低氧状态。许多必要的过程，如生产红细胞、调节能量和形成新的血液血管，受低氧的调节。阻塞性睡眠呼吸暂停综合征是一种非常常见的问题，与高血压有关。压力、糖尿病、记忆力差和心脏病发作。低氧导致低氧诱导因子表达上调 (高强度聚焦)。HIF-1和HIF-2是由于对促红细胞生成素(EPO)的研究而发现的，促红细胞生成素是刺激红系祖细胞并调节红血球的产生，这是PI之前退伍军人事务部支持。这一应用程序旨在获得对HIF的贡献的新见解，HIF监管红细胞生成，对阻塞性睡眠呼吸暂停综合征的病理生理学的影响。这项提案的PI令人感兴趣的是，与其他缺氧性疾病，他的主要临床/学术重点是红细胞增多症/红细胞增多症并不常见。 OSA的功能。在长时间低氧期间，HIF调节红细胞生成的增加，导致红细胞(RBC)块。当回到常氧状态时，增加的红细胞质量突然被过度校正缺氧形成的年轻红细胞的优先破坏，即溶血，这一现象被称为新细胞溶解。我们创造了一种新的小鼠新细胞溶解模型，并使用这个模型来显示新细胞溶解是由ROS的过度积累，红细胞内线粒体的增加，下调过氧化氢酶的microRNA miR-21增加。我们还获得了初步数据，表明新细胞溶解是预防的主要机制。阻塞性睡眠呼吸暂停综合征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本和活性降低，miR-21升高，这些水平随着 CPAP治疗。我们还观察到，在未矫正的OSA中，线粒体质量和ROS水平增加不仅在网织红细胞和成熟的红细胞中发现，而且在其他血细胞中也存在，如血小板、T细胞、B细胞。细胞、粒细胞和单核细胞。经CPAP治疗后，线粒体ROS降低，线粒体质量正常化。为了实现这项研究计划中概述的研究目标，我们将阐明OSA在利用外周血细胞证实HIF调节通路的初步发现大多数阻塞性睡眠呼吸暂停综合征患者继发于慢性间歇性低氧。我们将确定新陈代谢慢性间歇低氧与持续低氧对新生细胞溶解小鼠模型的影响及评估低氧血症的药理作用(S)。我们将评估一氧化碳(CO)的影响，它是通过溶血而增加的，对颈动脉小体(CB)的活性。CB是动脉的关键传感器血氧。低氧增加了来自CB的神经信号，而CB通过化学感觉反射控制呼吸和血压，这是对低氧的主要适应。增强的CB化学感觉反射在在阻塞性睡眠呼吸暂停综合征的病理生理学中发挥重要作用。新出现的证据表明，CB对缺氧的感觉涉及血红素加氧酶-2和氢产生的一氧化碳之间的血液氧依赖相互作用胱硫醚-ϒ-裂解酶合成硫化物。我们将使用呼出的一氧化碳呼气末呼气分析仪进行评估，阻塞性睡眠呼吸暂停综合征中溶血红细胞产生的CO增加是否会影响CB感觉和随后的化学感觉条件反射。