New Paradigms in the Design of Blood Substitutes

描述(由申请人提供)： 以血红蛋白为基础的氧气载体作为血液代用品的研究进展 桥接策略仍然是输血医学一个难以捉摸但亟需的目标。 HBOC引起的血管活动的并发症以及对其来源缺乏了解 这一效应以及HBOC和HbOCs在氧运输性质上的意外差异 RBC的，阻碍了它们的发展和部署。一款功能齐全、高度 由知名调查人员组成的生产性联盟提出了一个由 五个项目和一个核心将：1)揭示血管活动背后的潜在机制 与HBOC输注相关的并发症，2)测试HBOC设计的新范式 战略和3)为HBOC设计战略提供蓝图，以允许控制 血管活性和治疗应用的定制化。该计划建立在 已经建立的、正在进行的、非常成功的合作努力已经取得了成果 重要的新成果包括：系统规模的新的高产合成策略 聚乙二醇基表面修饰对血红蛋白的增强作用 生理研究表明，某些聚乙二醇化修饰的综合性能 血红蛋白导致血管活性的消除，一种新的自动调节模型来解释 用于血管活性和一系列生物物理结果，揭示功能和构象 不同大小增加的后果和改变的突变策略 血红蛋白。 该项目由弗里德曼博士担任私人侦探，将通过精心策划的 三大主题之间的相互作用：分子设计/合成，分子表征 和分子测试。该计划项目由五个项目和一个生化核心组成。 项目1(Acharya，AECOM)和项目2(Ho，Carnegie Mellon)将分别讨论基于化学和诱变修饰的设计策略。项目3(Friedman，AECOM)和项目4(Peisach，AECOM)将侧重于表面修饰和诱变的HBS的生物物理和功能特征。项目5(加州大学圣迭戈分校)将涵盖HBOCs的生理测试。通过项目1和项目2制定的战略设计的改良血红蛋白将在蛋白质生物化学核心(Manjula博士，AECOM)中生产并进行化学表征，项目2(核磁共振)、项目3(光学光谱和配体反应)、项目4(EPR)和项目5(生理学)所需的数量。

DESCRIPTION (provided by applicant): The development of hemoglobin-based oxygen carriers (HBOCs) as a blood replacement bridging strategy remains an elusive but much needed objective of transfusion medicine. Complications due HBOC induced vasoactivity and a lack of understanding as to the origins of this effect as well as unanticipated differences in oxygen transport properties of HBOCs and RBC's, have hindered their development and deployment. A fully functional and highly productive consortium of well-established investigators proposes a program project composed of five projects and one cores that will: 1) Expose the underlying mechanism behind vasoactivity complications associated with the infusion of HBOCs, 2) Test new paradigms for HBOC design strategies and 3) Provide a blue print for HBOC design strategies that will allow for the control of vasoactivity and customization for therapeutic applications. The program builds upon an established, on going and highly successful collaborative efforts that have already yielded important new results including: new high yield synthetic strategies for systematic size enhancement of hemoglobins based on surface decoration with polyethylene glycol (PEG), physiology studies showing that the colligative properties of certain PEG decorated hemoglobins result in the elimination of vasoactivity, a new auto-regulatory model to account for vasoactivity and a series of biophysical results that expose functional and conformational consequences of different size enhancement and mutagenic strategies for modifying hemoglobins. The program, with Dr. Friedman as the P.I., will achieve its objectives through an orchestrated interplay among three major themes: molecule design/synthesis, molecule characterization and molecule testing. The program project consists of five projects, and a biochemical core. Project 1 (Acharya, AECOM) and 2 (Ho, Carnegie Mellon) will primarily address design strategies based on chemical and mutagenic modifications respectively. Projects 3 (Friedman, AECOM) and 4 (Peisach, AECOM) will focus on biophysical and functional characterization of surface-decorated and mutagenized HbS. Project 5 (Intaglietta, UCSD) will cover physiological testing of HBOCs. Modified hemoglobins, designed through strategies developed from Projects 1 and 2, will be produced and chemically characterized in the Protein Biochemistry Core (Dr. Manjula, AECOM) in amounts needed for Projects 2(NMR), 3(optical spectroscopy and ligand reactivity), 4(EPR) and 5(physiology).