Restoration and Function of S-Nitrosothiol in Stored Blood
储存血液中S-亚硝基硫醇的恢复和作用
基本信息
- 批准号:9174571
- 负责人:
- 金额:$ 56.59万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2016
- 资助国家:美国
- 起止时间:2016-07-01 至 2021-06-30
- 项目状态:已结题
- 来源:
- 关键词:Advanced DevelopmentAdverse eventAnemiaAnimalsAutologousBloodBlood BanksBlood TransfusionBlood flowBreathingCarrying CapacitiesCessation of lifeClinicalClinical ChemistryClinical ResearchDataDevicesEnvironmental air flowErythrocytesEventFunctional disorderGoalsHemoglobinHemoglobin concentration resultHemorrhageHumanHypoxiaImpairmentInjuryKidneyLifeLightMeasuresMediatingMediator of activation proteinMethodsMicrocirculationModelingMolecularMusMutant Strains MiceMyocardial InfarctionNitric OxideOrganOxygenPatientsPerfusionPeripheralPersonal SatisfactionPhysiologicalPositioning AttributeProtocols documentationPublic HealthRoleRouteS-NitrosothiolsScienceSheepSignal TransductionStagingSystemTestingTherapeuticTimeTissuesTransfusionTranslatingTraumaVasodilationWild Type Mousebasedesigneffective therapyethyl nitritehealthy volunteerhuman tissueimprovedin vivoinsightmutantnovelpre-clinicalprognosticpublic health relevanceresearch clinical testingresponserestorationtherapeutic developmenttissue oxygenation
项目摘要
PROJECT SUMMARY
The therapeutic benefit of transfusion presumes a direct correlation between blood oxygen carrying capacity
and oxygen delivery. However, studies have shown that stored blood loses its ability to oxygenate tissues. The
sequelae that can occur after transfusion (renal injury, myocardial infarction, death) are consistent with the idea
that banked blood may exacerbate rather than correct anemia-induced hypoxia.
We have discovered that banked blood has markedly diminished levels of nitric oxide/S-nitrosothiol (NO/SNO)
bioactivity including reduced amounts of the S-nitrosylated form of hemoglobin (SNO-Hb), a major mediator of
blood flow and peripheral oxygen delivery. This decline in SNO provides a mechanistic basis for the impaired
vasodilatory activity of stored red blood cells (RBCs) and an explanation for why transfusion of even small
amounts of blood may impair tissue perfusion. We have built on this novel finding by demonstrating that
restoration of SNO-Hb levels (renitrosylation) corrects storage-induced deficiencies in RBC oxygen delivery
and transfusion-induced organ dysfunction in multiple preclinical transfusion paradigms, and we have initiated
clinical studies to assess the effects of transfusion on human tissue oxygenation. We have also developed
first-in-class renitrosylating agents that are already undergoing clinical testing.
We are positioned to provide critically needed data on the effects of transfusion on tissue oxygenation in
humans and to advance the benefits of renitrosylation therapy on oxygen delivery through the following aims:
1. To advance understanding of the molecular mechanisms by which RBCs deploy SNO-based signals to
regulate tissue oxygenation in fresh and stored blood.
2. To develop a device for ex vivo renitrosylation.
3. To determine if the physiologic responses to transfusion with renitrosylated RBCs are superior to
untreated banked blood in a preclinical trauma model.
4. To conduct an autologous standard flow (i.e. non-trauma) transfusion study in humans with and without
renitrosylation to delineate the physiologic effects of transfusion and the benefits of increased/restored
SNO-Hb levels on tissue oxygenation.
Collectively, our studies will provide much-needed insight into the effects of transfusion on tissue oxygenation,
shed light on the mechanistic basis of adverse ischemic events associated with transfusion, and accelerate
development of therapeutic approaches (repletion of SNO-Hb). Restoration of the oxygen delivery capabilities
of banked blood should result in blood transfusion achieving its clinical purpose: vasodilation in the
microcirculation to improve end-organ oxygen delivery in the anemic patient. To the extent that the world's
supplies of banked RBCs are deficient in SNO-Hb, renitrosylation may hold significant therapeutic promise.
项目摘要
输血的治疗益处假定血液携氧能力与
和氧气输送。然而,研究表明,储存的血液失去了它的能力,使组织。的
输血后可能发生的后遗症(肾损伤、心肌梗死、死亡)与这一想法一致
库存血液可能会加剧而不是纠正贫血引起的缺氧。
我们已经发现,库存血液具有显着降低一氧化氮/S-亚硝基硫醇(NO/SNO)的水平,
生物活性,包括减少量的S-亚硝基化形式的血红蛋白(SNO-Hb),一种主要的介体,
血流和外周氧输送。SNO的这种下降为受损的
储存的红细胞(RBC)的血管舒张活性,以及为什么即使是很小的输血
大量的血液可能损害组织灌注。我们在这一新发现的基础上,
SNO-Hb水平的恢复(再亚硝基化)纠正了储存引起的RBC氧输送不足
和输血引起的器官功能障碍在多种临床前输血范例,我们已经开始
评估输血对人体组织氧合影响的临床研究。我们还开发了
已经在进行临床测试的一流的再亚硝基化剂。
我们的定位是提供急需的数据,输血对组织氧合的影响,
并通过以下目的提高再亚硝基化疗法对氧气输送的益处:
1.为了进一步了解RBC部署基于SNO的信号的分子机制,
调节新鲜和储存血液中的组织氧合。
2.开发一种离体再亚硝基化装置。
3.确定输注再亚硝基化RBC的生理反应是否优于上级
在临床前创伤模型中未处理的库存血液。
4.在有和没有自体标准流量(即非创伤)输血的人体中进行自体标准流量(即非创伤)输血研究
重新亚硝基化以描述输血的生理效应和增加/恢复的益处
SNO-Hb水平对组织氧合的影响。
总的来说,我们的研究将为输血对组织氧合的影响提供急需的见解,
阐明与输血相关的不良缺血事件的机制基础,并加速
开发治疗方法(补充SNO-Hb)。恢复氧气输送能力
库血的储存应导致输血达到其临床目的:
微循环,以改善贫血患者的终末器官氧输送。在某种程度上,
库存红细胞的供应缺乏SNO-Hb,再亚硝基化可能具有重要的治疗前景。
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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JONATHAN S. STAMLER其他文献
JONATHAN S. STAMLER的其他文献
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{{ truncateString('JONATHAN S. STAMLER', 18)}}的其他基金
Gut Microbe-Derived Nitric Oxide As A Signal To Host: Role In Normal Physiology And In Disease
肠道微生物衍生的一氧化氮作为宿主信号:在正常生理和疾病中的作用
- 批准号:
10184663 - 财政年份:2021
- 资助金额:
$ 56.59万 - 项目类别:
Gut Microbe-Derived Nitric Oxide As A Signal To Host: Role In Normal Physiology And In Disease
肠道微生物衍生的一氧化氮作为宿主信号:在正常生理和疾病中的作用
- 批准号:
10576352 - 财政年份:2021
- 资助金额:
$ 56.59万 - 项目类别:
Gut Microbe-Derived Nitric Oxide As A Signal To Host: Role In Normal Physiology And In Disease
肠道微生物衍生的一氧化氮作为宿主信号:在正常生理和疾病中的作用
- 批准号:
10357961 - 财政年份:2021
- 资助金额:
$ 56.59万 - 项目类别:
Novel Regulation of Renal Function by S-Nitrosylation
S-亚硝基化对肾功能的新调节
- 批准号:
9792377 - 财政年份:2018
- 资助金额:
$ 56.59万 - 项目类别:
Novel Regulation of Renal Function by S-Nitrosylation
S-亚硝基化对肾功能的新调节
- 批准号:
10453693 - 财政年份:2018
- 资助金额:
$ 56.59万 - 项目类别:
Novel Regulation of Renal Function by S-Nitrosylation
S-亚硝基化对肾功能的新调节
- 批准号:
10223283 - 财政年份:2018
- 资助金额:
$ 56.59万 - 项目类别:
Restoration and Function of S-Nitrosothiol in Stored Blood
储存血液中S-亚硝基硫醇的恢复和作用
- 批准号:
10586343 - 财政年份:2016
- 资助金额:
$ 56.59万 - 项目类别:
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