Erythrocyte metabolomic profiling reveals new insight and approaches to promote oxygen delivery

红细胞代谢组学分析揭示了促进氧输送的新见解和方法

基本信息

批准号：
9240402
负责人：
Yang Xia
金额：
$ 38.1万
依托单位：
UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
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 2020-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9240402
关键词：
Adenosine Affinity Altitude Angiotensin II Binding Body Regions Cardiac Cardiovascular Diseases Cardiovascular system Cessation of life Collaborations Coupled Dangerousness Development Disease Environment Erythrocytes Erythroid Exercise Experimental Models FDA approved Failure Functional disorder Funding Genetic study Glycolysis Goals Hemoglobin Human Human Volunteers Hypoxia Individual Injury Innovative Therapy Knock-out Knowledge Mediating Metabolic Metabolic Pathway Mission Modeling Molecular Morbidity - disease rate Mus Organ Oxygen Pathway interactions Patients Performance Pharmaceutical Preparations Pharmacology Plasma Production Proteomics Publishing Pulmonary Edema Research Role Signal Pathway Signal Transduction Stroke Techniques Therapeutic Therapeutic Effect Tissues Translating United States National Institutes of Health Vascular Diseases Work base cognitive function follow-up genetic approach improved innovation insight metabolomics mortality multidisciplinary novel novel strategies novel therapeutics pre-clinical preclinical study prevent respiratory response sensor sphingosine 1-phosphate therapeutic evaluation therapeutic target therapy design translational study

项目摘要

The goal of proposed research is the development of novel approaches to ameliorate hypoxia-induced tissue damage. As an important mission of NIH is to develop highly innovative treatments to prevent tissue hypoxia, progression and death, the goal of the proposed work should be of high priority. Research proposed here is based on unexpected discoveries resulting from an unbiased, high-throughput metabolomic screen revealing that the metabolic pathway responsible for the production of erythrocyte 2,3-bisphosphoglycerate (2,3-BPG), a glycolytic erythroid byproduct known to reduce hemoglobin (Hb)-O2 binding affinity, sphingosine-1-phosphate (S1P), a highly enriched erythrocyte biolipid, and plasma adenosine, a hypoxic and energy sensor, were rapidly induced in 21 young healthy human volunteers at high altitude. Significantly, the elevation of these three metabolites was associated with the quick increase of O2 release capacity mediated by high altitude. Follow-up mouse genetic studies demonstrated that in two independent experimental models, one mimicking high altitude hypoxia and the other associated with cardiac vascular diseases, ADORA2B-mediated 2,3-BPG induction and O2 delivery has a general protective role in hypoxic tissue damage. Mechanistically, we discovered that AMPK, a known cellular energy sensor, functioned downstream of ADORA2B underlying adenosine induced 2,3-BPG production and O2 delivery. Intriguingly, we discovered that ADORA2B signaling also induces activation of erythrocyte SphK1 and that elevated SphK1-induced production of S1P functions intracellularlly to promote 2,3- BPG and O2 delivery to counteract tissue hypoxia. Functional and structural studies revealed that S1P binds Hb and synergistically works together with 2,3-BPG to further decrease Hb-O2 binding affinity and thus stabilizes deoxyHb. Overall, our published and unpublished findings raise intriguing hypotheses that elevated erythrocyte adenosine-ADORA2B-AMPK and SphK1-S1P signaling networks function collaboratively to counteract hypoxia by inducing 2,3-BPG production and O2 delivery. The project has interrelated goals to translate our findings into innovative therapeutics to treat and prevent hypoxia by providing new insight into mechanisms for hypoxia adaptation. To extend our discoveries of the protective role of these newly identified hypoxia-induced metabolites and signaling cascades, we will conduct preclinical studies (AIM I) by testing the therapeutic effects of multiple FDA approved drugs on tissue hypoxia in two independent models. AIMs II and III include pharmacological and novel genetic approaches coupled with robust innovative proteomic and metabolomic techniques to assess how AMPK and S1P-mediated hypoxic erythrocyte metabolic reprogramming to rapidly induce 2,3-BPG and O2 release. Finally, we will conduct human translational studies by collaboration with ongoing DOD funded projects to further define if AMPK and SphK1 activities are induced by high altitude hypoxia and correlated with improved cognitive function and exercise performance (AIM IV). Overall, the proposed studies are aimed to reveal important therapeutic targets in the management of high altitude and diseases associated with hypoxia.

拟议研究的目标是开发改善缺氧引起的组织的新方法损害。 NIH 的一项重要使命是开发高度创新的治疗方法来预防组织缺氧，进展和死亡，拟议工作的目标应该是高度优先的。这里提出的研究是基于公正的高通量代谢组学筛选得出的意外发现负责产生红细胞 2,3-二磷酸甘油酸 (2,3-BPG) 的代谢途径已知可降低血红蛋白 (Hb)-O2 结合亲和力的糖酵解红系副产物，1-磷酸鞘氨醇 (S1P)（一种高度富集的红细胞生物脂质）和血浆腺苷（一种缺氧和能量传感器）迅速被 21 名年轻健康志愿者在高海拔地区进行诱导。值得注意的是，这三者的提升代谢物与高海拔介导的 O2 释放能力的快速增加有关。跟进小鼠遗传学研究表明，在两个独立的实验模型中，其中一个模仿高海拔缺氧和其他与心血管疾病相关的疾病，ADORA2B 介导的 2,3-BPG 诱导和氧气输送对缺氧组织损伤具有一般保护作用。从机制上讲，我们发现 AMPK，一种已知的细胞能量传感器，在腺苷诱导的 2,3-BPG 的 ADORA2B 下游发挥作用生产和氧气输送。有趣的是，我们发现 ADORA2B 信号传导还诱导激活红细胞 SphK1 和增加 SphK1 诱导的 S1P 产生在细胞内发挥作用，促进 2,3- BPG 和 O2 输送可抵消组织缺氧。功能和结构研究表明 S1P 结合 Hb 与2,3-BPG协同作用，进一步降低Hb-O2结合亲和力，从而稳定脱氧血红蛋白。总体而言，我们已发表和未发表的研究结果提出了有趣的假设，即红细胞升高腺苷-ADORA2B-AMPK 和 SphK1-S1P 信号网络协同发挥作用，抵抗缺氧通过诱导 2,3-BPG 产生和 O2 输送。该项目具有相互关联的目标，可将我们的发现转化为通过提供对缺氧机制的新见解来治疗和预防缺氧的创新疗法适应。扩展我们对这些新发现的缺氧诱导代谢物的保护作用的发现和信号级联反应，我们将通过测试多种药物的治疗效果来进行临床前研究（AIM I） FDA 批准了在两个独立模型中治疗组织缺氧的药物。目标 II 和 III 包括药理学和新颖的遗传方法加上强大的创新蛋白质组学和代谢组学技术来评估如何 AMPK 和 S1P 介导的缺氧红细胞代谢重编程快速诱导 2,3-BPG 和 O2 发布。最后，我们将与正在进行的国防部资助项目合作进行人类转化研究进一步确定 AMPK 和 SphK1 活性是否由高原缺氧诱导并与改善相关认知功能和运动表现（AIM IV）。总体而言，拟议的研究旨在揭示管理高海拔和缺氧相关疾病的重要治疗目标。