MECHANISMS AND MODULATION OF ACCELLULAR HbA TOXICITY

细胞 HbA 毒性的机制和调节

• 批准号: 9127328
• 负责人: JOEL M FRIEDMAN
• 金额: $ 213.67万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE, INC
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-01 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9127328
• 关键词: Acute; Acute Disease; Adverse effects; Adverse event; Animal Model; Animals; Autologous; Binding; Biochemical; Biological Models; Blood; Blood Transfusion; Blood capillaries; Cell Volumes; Chemicals; Chronic; Chronic Disease; Clinical; Clinical Trials; Core Facility; Engineering; Erythrocytes; Evaluation; Failure; Generations; Goals; Haptoglobins; Hematology; Hemoglobin; Hemoglobinopathies; Hemolysis; Hemorrhagic Shock; Inflammation; Infusion procedures; Injection of therapeutic agent; Medicine; Modification; Organ; Outcome; Oxygen; Patients; Perfusion; Physiological; Plasma; Precipitation; Production; Property; Reaction; Recombinants; Reducing Agents; Rice; Testing; Therapeutic; Therapeutic Uses; Tissue Expansion; Toxic effect; Transfusion; Vascular Diseases; base; capillary; chemical reaction; extracellular; in vivo; nanoparticle; oxidation; pathogen; polymerization; prevent; programs

DESCRIPTION (provided by applicant): This program seeks to determine the mechanisms responsible for toxicities associated with acellular hemoglobins (Hbs) in blood and to establish strategies to prevent or reverse these toxicities. The results will have a significant impact on hematology and transfusion medicine by: (1) providing rational therapies to minimize the clinical problems associated with Hb released from autologous, hemolyzed red blood cells in patients with chronic or acute diseases and from heterologous stored blood used for transfusions and (2) Identifying the underlying causes of the commercial failure of extracellular Hb-based oxygen carriers (HBOCs), providing strategies to mitigate or eliminate these problems, and optimizing their efficacy for volume expansion and tissue perfusion with reduced toxicity. A long term goal is to provide safer and more effective blood transfusions using therapeutic options that match transfusion strategies with clinical needs and availability of fresh stored blood. These objectives will be achieved through 3 projects, and 4 core facilities. Project 1 (UCSD, M. Intaglietta, PI) wil use microvascular perfusion markers to identity Hb-related changes in capillary function and examine Hb toxicity during acute and chronic vascular dysfunction. Project 2 (Rice U., J. Olson, PI and A. Alayash, FDA) will engineer recombinant Hb with varied (high/low) 02 binding, NO dioxygenation, oxidation, and denaturation properties and use them to test the importance of NO scavenging, oxidative degradation, denaturation and precipitation, and impaired clearance in causing plasma Hb toxicity in cellular, organ, and whole animal model systems. Project 3 (AECOM, J. Friedman, PI) will evaluate whether PEGylation or polymerization of Hb, generation of bioactive NO by Hb, injection of nanoparticles releasing NO or GSNO, and the infusion of reducing agents and haptoglobin can be used effectively to limit toxicity derived from the oxidative reactions of acellular Hb. The four Cores are: Core A, Administrative unit (AECOM, Friedman, PI); Core B, HbA Chemical Modifications and Nanoparticle Production (AECOM, Nacharaju, leader); Core C, Recombinant HbA Production for In Vivo Toxicity Studies (Rice U. Olson, leader); Core D, Chemical, Cellular, And Animal Toxicity Evaluations (FDA, Alayash leader)

描述（由申请人提供）：该计划旨在确定与血液中与细胞细胞血红蛋白（HB）相关的毒性的机制，并制定预防或逆转这些毒性的策略。结果将对血液学和输血医学产生重大影响：（1）提供合理的治疗方法，以最大程度地减少与慢性或急性疾病患者自体，溶血性红细胞相关的临床问题，以及用于过渡的异质储存的血液以及（2）确定基于量子的HB的近乎疾病的血液，并识别出基于量子的HB，并确定（2）量子。减轻或消除这些问题的策略，并通过降低毒性来优化其体积膨胀和组织灌注的功效。一个长期的目标是使用治疗选择与输血策略与临床需求和新鲜储存的血液的可用性相匹配，提供更安全，更有效的输血。这些目标将通过3个项目和4个核心设施实现。项目1（UCSD，M。Intaglietta，PI）将使用微血管灌注标记来对毛细血管功能的身份变化，并检查急性和慢性血管功能障碍期间的HB毒性。 Project 2 (Rice U., J. Olson, PI and A. Alayash, FDA) will engineer recombinant Hb with varied (high/low) 02 binding, NO dioxygenation, oxidation, and denaturation properties and use them to test the importance of NO scavenging, oxidative degradation, denaturation and precipitation, and impaired clearance in causing plasma Hb toxicity in cellular, organ, and whole animal模型系统。项目3（AECOM，J。Friedman，PI）将评估HB的质量或聚合，HB的生物活性NO的产生，注射NO或GSNO的纳米颗粒以及降低剂的输注和脱蛋白的输注可以有效地从氧化反应中限制氧化反应。这四个核心是：核心A，行政部门（Aecom，Friedman，pi）；核心B，HBA化学修饰和纳米颗粒产生（Aecom，Nacharaju，领导者）； Core C，重组HBA生产体内毒性研究（Rice U. Olson，领导者）；核心D，化学，细胞和动物毒性评估（FDA，Alayash领导者）

项目成果

Reverse micelles as a tool for probing solvent modulation of protein dynamics: Reverse micelle encapsulated hemoglobin.

反胶束作为探测蛋白质动力学溶剂调节的工具：反胶束封装的血红蛋白。

• DOI: 10.1016/j.chemphys.2013.04.006
• 发表时间: 2013
• 期刊: Chemical physics
• 影响因子: 2.3
• 作者: Roche,CamilleJ;Dantsker,David;Heller,ElizabethR;Sabat,JosephE;Friedman,JoelM
• 通讯作者: Friedman,JoelM

Hemoglobin-Based Blood Substitutes and the Treatment of Sickle Cell Disease: More Harm than Help?

• DOI: 10.3390/biom7010002
• 发表时间: 2017-03-01
• 期刊: BIOMOLECULES
• 影响因子: 5.5
• 作者: Alayash, Abdu I.

Supra-plasma expanders: the future of treating blood loss and anemia without red cell transfusions?

• DOI: 10.1097/nan.0000000000000103
• 发表时间: 2015-05
• 期刊: Journal of infusion nursing : the official publication of the Infusion Nurses Society
• 作者: Tsai AG;Vázquez BY;Hofmann A;Acharya SA;Intaglietta M
• 通讯作者: Intaglietta M

Cardiac-specific knockout and pharmacological inhibition of Endothelin receptor type B lead to cardiac resistance to extreme hypoxia.

• DOI: 10.1007/s00109-018-1673-2
• 发表时间: 2018-09
• 期刊: Journal of molecular medicine (Berlin, Germany)
• 作者: Stobdan T;Zhou D;Williams AT;Cabrales P;Haddad GG
• 通讯作者: Haddad GG

Oxidized Mutant Human Hemoglobins S and E Induce Oxidative Stress and Bioenergetic Dysfunction in Human Pulmonary Endothelial Cells.

• DOI: 10.3389/fphys.2017.01082
• 发表时间: 2017
• 期刊: Frontiers in physiology
• 影响因子: 4
• 作者: Jana S;Meng F;Hirsch RE;Friedman JM;Alayash AI
• 通讯作者: Alayash AI