Interactions between the ADORA2b/Sphk1axis and the AE1-Hb switch in red blood cell aging in vivo and in vitro
ADORA2b/Sphk1axis 和 AE1-Hb 开关在体内和体外红细胞老化中的相互作用
基本信息
- 批准号:10369002
- 负责人:
- 金额:$ 63.65万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-03-15 至 2024-02-29
- 项目状态:已结题
- 来源:
- 关键词:AcclimatizationAdenosineAdenosine A2B ReceptorAffectAffinityAgeAgingAldehyde-LyasesAltitudeAmericanAnimal ModelAnionsAntigensAntioxidantsBindingBiochemicalBloodBlood BanksBlood CirculationBlood TransfusionBlood donorCell AgingCell NucleusCell SurvivalCellsCellular Metabolic ProcessCellular biologyChloridesComplexCytolysisCytosolDataDiseaseDockingEnergy MetabolismEnzymesErythrocyte TransfusionErythrocytesExposure toFaceFunctional disorderGene Expression RegulationGlucoseGlucosephosphate DehydrogenaseGlucosephosphate Dehydrogenase DeficiencyGlyceraldehyde-3-Phosphate DehydrogenasesGlycolysisHealthHemoglobinHospitalsHourHumanHuman bodyHypoxiaIn VitroIndividualInterventionIronLifeLogisticsLongevityLungMedicalMembraneMetabolicMetabolic stressMetabolismModificationMorphologyMusN-terminalNADHNADPOrganellesOxidation-ReductionOxidative StressOxygenPathologicPathologyPathway interactionsPatientsPentosephosphate PathwayPeripheralPersonsPlasmaPlayPredispositionProceduresProteinsProteomicsReactionRoleSPHK1 enzymeSavingsSeaSeriesSickle Cell AnemiaSignal TransductionSiteTechnologyTissuesTranslationsVaccinationage relatedbasecell agecofactordeoxyhemoglobindiphosphoglycerategene productin vivomouse modelnormoxianoveloxidant stressoxidative damagerepairedresponsesenescencesensortool
项目摘要
ABSTRACT
Red Blood Cells (RBCs) represent ~83% of the total human cells in the body. RBC hemoglobin (Hb), which is
critical for their function to carry and deliver oxygen to peripheral tissues, constitutes ~90% of the total protein
content of a mature RBCs. During their lifespan of 120 days in the bloodstream, RBCs are constantly exposed
to oxidant stress, which mostly arises from Fenton and Haber-Weiss reactions triggered by Hb-Iron in the
presence of oxygen. However, RBCs lack nuclei and organelle and, as such, they cannot synthesize new
proteins to replace oxidatively damaged components. Therefore, in order to cope with oxidant stress, RBCs have
evolved unique mechanisms that rely on signaling axes and their capacity to trigger metabolic reprogramming
to favor antioxidant defenses (the Pentose Phosphate Pathway – PPP) over energy metabolism (glycolysis).
One such mechanism relies on the two most abundant proteins in RBC cytosols and membranes: Hb and anion
exchanger 1 (AE1), respectively. Owing to its capacity to “sense” oxygen, in response to hypoxia, deoxygenated
Hb migrates to the membrane, where it binds the N-terminus of AE1. This mechanism releases a series of
glycolytic enzymes, which are inhibited under high-oxygen tensions owing to their binding to the same region of
AE1 with high affinity for deoxygenated Hb. This phenomenon favors energy metabolism under low oxygen
tensions (e.g., high-altitude hypoxia), while it creates a metabolic bottleneck in energy metabolism to promote a
critical antioxidant pathway when oxidant stress is high: the Pentose Phosphate Pathway (PPP). This
mechanism is referred to as the AE1-Hb switch in this proposal. Of note, glucose 6-phosphate dehydrogenase
(G6PD) is not only the rate-limiting enzyme of the PPP, but also the target of the most common enzymopathy in
humans, G6PD deficiency, which affects ~400 million people. While RBCs from G6PD-deficient subjects are
perfectly healthy in the absence of oxidant stress, RBCs from these individuals are characterized by a shorter
lifespan and susceptibility to lysis following oxidative insults. Oxidative stress to RBCs is not only relevant within
the context of RBC senescence. Significant oxidant stress arises during RBC storage under blood bank
conditions for blood transfusion purposes, a common in hospital medical procedure and a life-saving intervention
for ~3-4 million Americans every year. However, little is known about the impact of the AE1-Hb switch and G6PD
deficiency in the context of RBC aging in vitro (blood bank). In parallel, when studying human acclimatization to
high-altitude hypoxia, we discovered a novel axis, the ADORA2b/Sphk1 axis, that interplays with the AE1-Hb
switch to favor oxygen off-loading in healthy individuals as they climb to high-altitude, where oxygen is limited in
comparison to sea level. By leveraging a combination of state-of-the art omics technologies (fluxomics and
Xlinking proteomics) and a mix of well-established and novel animal models (exclusively developed for this
proposal – e.g., G6PD-def mice) we will investigate the interplay of the AE1-Hb switch and ADORA2b/Sphk1 in
the context of oxidant stress and hypoxia during RBC aging in vivo (senescence) and in vitro (blood bank).
摘要
红细胞(RBC)占人体细胞总数的83%。红细胞血红蛋白(Hb),这是
对它们向外周组织运送和输送氧气的功能至关重要,占总蛋白的90%
一个成熟的红细胞的含量。红细胞在血液中的寿命为120天,不断地暴露在
氧化应激,主要由Hb-Fe引发的Fenton和Haber-Weiss反应引起
氧气的存在。然而,红细胞缺乏细胞核和细胞器,因此不能合成新的
取代氧化损伤成分的蛋白质。因此,为了应对氧化应激,红细胞已经
进化出独特的机制,依赖于信号轴及其触发代谢重新编程的能力
支持抗氧化剂防御(磷酸戊糖途径-PPP)而不是能量代谢(糖酵解)。
其中一种机制依赖于红细胞胞浆和细胞膜中含量最丰富的两种蛋白质:Hb和阴离子。
交易所1(AE1)。由于它的“感觉”氧气的能力,在低氧的反应下,脱氧
Hb迁移到膜上,在那里它与AE1的N末端结合。这一机制释放了一系列
糖酵解酶,在高氧压力下被抑制,因为它们与
对脱氧Hb具有高亲和力的AE1。这种现象有利于低氧条件下的能量代谢。
紧张(例如,高海拔低氧),虽然它在能量代谢中造成代谢瓶颈,以促进
氧化应激高时的关键抗氧化途径:磷酸戊糖途径(PPP)。这
该机制在本提案中称为AE1-HB交换机。值得注意的是,葡萄糖6-磷酸脱氢酶
(G6PD)不仅是PPP的限速酶,也是PPP中最常见的酶病靶点。
人类,G6PD缺乏症,影响到约4亿人。而来自G6PD缺陷受试者的红细胞是
在没有氧化应激的情况下非常健康,这些个体的红细胞特征是较短
寿命和对氧化侮辱后溶解的敏感性。氧化应激对红细胞的影响不仅与
红细胞衰老的背景。红细胞在血库下储存过程中会产生明显的氧化应激
输血条件,医院常见的医疗程序和救命干预措施
每年约有300-400万美国人。然而,人们对AE1-HB开关和G6PD的影响知之甚少
红细胞体外老化背景下的缺陷(血库)。同时,在研究人类适应时
在高原缺氧时,我们发现了一个新的轴,ADORA2b/Sphk1轴,它与AE1-Hb相互作用
在健康的个体攀登到高海拔时,转向支持氧气卸载,在那里氧气被限制在
与海平面相比。通过利用最先进的组学技术(通量组学和
Xlink蛋白质组学)和成熟的和新的动物模型的组合(专门为此而开发
建议--例如,G6PD-def小鼠)我们将研究AE1-Hb开关和ADORA2b/Sphk1在
体内(衰老)和体外(血库)红细胞老化过程中氧化应激和缺氧的背景。
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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Angelo D'Alessandro其他文献
Angelo D'Alessandro的其他文献
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{{ truncateString('Angelo D'Alessandro', 18)}}的其他基金
Investigating metabolic responses to high sugar diets and the onset of diabetic phenotypes
研究对高糖饮食的代谢反应和糖尿病表型的发生
- 批准号:
10719544 - 财政年份:2023
- 资助金额:
$ 63.65万 - 项目类别:
Interactions between the ADORA2b/Sphk1axis and the AE1-Hb switch in red blood cell aging in vivo and in vitro
ADORA2b/Sphk1axis 和 AE1-Hb 开关在体内和体外红细胞老化中的相互作用
- 批准号:
10580716 - 财政年份:2020
- 资助金额:
$ 63.65万 - 项目类别:
The Impact of Oxidative Stress on Erythocyte Biology
氧化应激对红细胞生物学的影响
- 批准号:
10252033 - 财政年份:2019
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$ 63.65万 - 项目类别:
The Impact of Oxidative Stress on Erythocyte Biology
氧化应激对红细胞生物学的影响
- 批准号:
10487440 - 财政年份:2019
- 资助金额:
$ 63.65万 - 项目类别:
PIMT1 in Red Blood Cell aging in vivo and in vitro
PIMT1在体内和体外红细胞老化中的作用
- 批准号:
10405591 - 财政年份:2019
- 资助金额:
$ 63.65万 - 项目类别:
PIMT1 in Red Blood Cell aging in vivo and in vitro
PIMT1在体内和体外红细胞老化中的作用
- 批准号:
10605316 - 财政年份:2019
- 资助金额:
$ 63.65万 - 项目类别:
PIMT1 in Red Blood Cell aging in vivo and in vitro
PIMT1在体内和体外红细胞老化中的作用
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9983156 - 财政年份:2019
- 资助金额:
$ 63.65万 - 项目类别:
The Impact of Oxidative Stress on Erythocyte Biology
氧化应激对红细胞生物学的影响
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10022515 - 财政年份:2019
- 资助金额:
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