MECHANISMS AND MODULATION OF ACCELLULAR HbA TOXICITY

细胞 HbA 毒性的机制和调节

• 批准号: 8707839
• 负责人: JOEL M FRIEDMAN
• 金额: $ 208.75万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 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 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8707839
• 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无细胞血红蛋白 (Hbs) 相关的毒性的机制，并制定预防或逆转这些毒性的策略。研究结果将对血液学和输血医学产生重大影响，具体体现在：(1) 提供合理的治疗方法，最大限度地减少与慢性或急性疾病患者的自体溶血红细胞以及用于治疗目的的异源储存血液中释放的 Hb 相关的临床问题。 (2) 确定细胞外血红蛋白氧载体 (HBOC) 商业失败的根本原因，提供缓解或消除这些问题的策略，并优化其扩容和组织灌注的功效，减少毒性。长期目标是使用将输血策略与临床需求和新鲜储存血液的可用性相匹配的治疗方案来提供更安全、更有效的输血。这些目标将通过3个项目和4个核心设施来实现。项目 1（UCSD、M. Intaglietta、PI）将使用微血管灌注标记物来识别与 Hb 相关的毛细血管功能变化，并检查急性和慢性血管功能障碍期间的 Hb 毒性。项目 2（Rice U.、J. Olson、PI 和 A. Alayash，FDA）将设计具有不同（高/低）O2 结合、NO 双氧合、氧化和变性特性的重组 Hb，并用它们来测试 NO 的重要性清除、氧化降解、变性和沉淀以及清除受损导致细胞、器官和整个动物模型系统中血浆 Hb 毒性。项目3（AECOM，J. Friedman，PI）将评估Hb的聚乙二醇化或聚合、Hb生成生物活性NO、注射释放NO或GSNO的纳米粒子以及输注还原剂和触珠蛋白是否可以有效地限制毒性源自非细胞 Hb 的氧化反应。四个核心是： 核心 A，行政单位（AECOM、Friedman、PI）；核心 B，HbA1c 化学修饰和纳米颗粒生产（AECOM，Nacharaju，领导者）；核心 C，用于体内毒性研究的重组 HbA 生产（Rice U. Olson，负责人）；核心 D，化学、细胞和动物毒性评估（FDA，Alayash 领导者）