Evaluation of Invertebrate Hemoglobins as Effective, Safe, and Ultra-Stable Blood Substitutes

无脊椎动物血红蛋白作为有效、安全和超稳定血液替代品的评估

• 批准号: 9305265
• 负责人: Jacob James Elmer
• 金额: $ 43.24万
• 依托单位: VILLANOVA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9305265
• 关键词: Address; Adverse effects; Affinity; Anemia; Animal Experiments; Antioxidants; Area; Biomedical Research; Blood; Blood Circulation; Blood Coagulation Disorders; Blood Substitutes; Buffers; Cattle; Chemicals; Chronic; Clinical Trials; Collaborations; Complement; Data; Developing Countries; Development; Emergency Situation; Environment; Erythrocytes; Evaluation; Exhibits; FBLN5 gene; Freeze Drying; Funding; Funding Mechanisms; Goals; Half-Life; Hamsters; Hemoglobin; Hemolysis; Hemorrhage; High temperature of physical object; Hospitals; Human; Hypertension; Hypoxia; Inflammation; Institution; Invertebrates; Ischemia; Long-Term Effects; Lumbricus terrestris; Measures; Metabolic Clearance Rate; Military Personnel; Mission; Monitor; Mus; Myocardial Infarction; National Heart, Lung, and Blood Institute; Organ; Oxidative Stress; Oxygen; Patients; Pediatric Hospitals; Philadelphia; Precipitation; Problem Solving; Property; Proteins; Protocols documentation; Refrigeration; Research; Research Personnel; Resources; Resuscitation; Safety; Sickle Cell Anemia; Signal Transduction; Stroke; Temperature; Testing; Thalassemia; Time; Tissues; Transfusion; Universities; Work; base; beta Thalassemia; career; design; drug development; drug discovery; effective therapy; experience; extracellular; improved; in vivo; light weight; loss of function; mouse model; novel; oxidation; oxygen transport; portability; undergraduate student

Project Summary Transfusions of donated blood are the safest and most effective way to treat a patient with severe blood loss. However, there are many situations (e.g. military battlefields, remote areas, developing countries) in which blood is unavailable because it must be constantly refrigerated. The purpose of this project is to develop a “blood substitute” that does not require refrigeration and can be deployed to save lives in remote areas. Most previous blood substitutes have been based on purified human hemoglobin, since it is a protein that does not require refrigeration and it is responsible for the most vital function of human blood – oxygen transport. Unfortunately, clinical trials have revealed that blood substitutes based on human hemoglobin cause many different serious side effects, including heart attack and stroke. The goal of this project is to find an alternative hemoglobin that can effectively transport oxygen without causing the side effects observed with human hemoglobin. Specifically, the efficacy and safety of 2 invertebrate hemoglobins with unique properties will be investigated by transfusing them into mice. The effects of long term storage (>1-2 weeks) at high temperatures (70-140oF) on each of the hemoglobins will also be investigated to determine if they can be deployed to remote areas where donated blood is unavailable. Finally, the hemoglobins will be chemically modified to increase their stability and a freeze drying protocol will be developed to produce a blood substitute that is ultra- stable and ultra-portable. This work will enhance the research environment at Villanova University by establishing a valuable collaboration with experienced researchers at the Children's Hospital of Philadelphia. This project will also provide support for at least 1 graduate and 12 undergraduate students to gain valuable research experience in the field of drug discovery and development by working at both Villanova and CHOP.

项目摘要 输注捐献的血液是最安全和最有效的方法来治疗病人， 严重失血然而，有许多情况（例如，军事战场，偏远地区， 发展中国家），因为血液必须不断冷藏而无法获得。的 该项目的目的是开发一种“血液替代品”，不需要冷藏， 在偏远地区拯救生命。 大多数以前的血液替代品都是基于纯化的人类血红蛋白，因为它是一种 不需要冷藏的蛋白质，它负责人体最重要的功能 血氧运输。不幸的是，临床试验表明，基于 人类血红蛋白会引起许多不同严重副作用，包括心脏病发作和中风。的 该项目的目标是找到一种替代血红蛋白，可以有效地运输氧气， 导致了在人血红蛋白中观察到的副作用。具体而言，2的有效性和安全性 将具有独特性质的无脊椎动物血红蛋白通过将其植入小鼠体内进行研究。 在高温（70- 140 oF）下长期储存（>1-2周）对每种 血红蛋白也将被调查，以确定他们是否可以部署到偏远地区， 捐献的血液无法获得。最后，血红蛋白将被化学修饰，以增加其 稳定性和冷冻干燥方案将被开发，以生产超 稳定且超便携。 这项工作将通过建立一个 与费城儿童医院经验丰富的研究人员进行了宝贵的合作。这 项目还将提供至少1个研究生和12个本科生获得支持 在药物发现和开发领域的宝贵研究经验， 维拉诺瓦和CHOP。

项目成果

Increasing the stability of Lumbricus terrestris erythrocruorin via poly(acrylic acid) conjugation.

通过聚（丙烯酸）结合来提高lumbricus terrestris rethrothocruorin的稳定性。

• DOI: 10.1080/21691401.2018.1480491
• 发表时间: 2018
• 期刊: Artificial cells, nanomedicine, and biotechnology
• 作者: Spivack K;Tucker M;Zimmerman D;Nicholas M;Abdulmalik O;Comolli N;Elmer J
• 通讯作者: Elmer J

Purification of Lumbricus terrestris erythrocruorin (LtEc) with anion exchange chromatography.

使用阴离子交换色谱法纯化 Lumbricus terrestris erythrocruorin (LtEc)。

• DOI: 10.1016/j.jchromb.2020.122162
• 发表时间: 2020
• 期刊: Journal of chromatography. B, Analytical technologies in the biomedical and life sciences
• 作者: Timm,Brandon;Abdulmalik,Osheiza;Chakrabarti,Atis;Elmer,Jacob
• 通讯作者: Elmer,Jacob