New Paradigms in the Design of Blood Substitutes

描述（由申请人提供）： 血红蛋白氧载体（HBOCs）作为血液替代物的发展 桥接策略仍然是输血医学的一个难以捉摸但急需的目标。 由于HBOC引起的血管活性并发症以及对HBOC的起源缺乏了解， 这种效应以及HBOCs的氧传输特性的意外差异， RBC的，阻碍了他们的发展和部署。一个功能齐全， 一个由知名调查人员组成的富有成效的财团提出了一个项目， 五个项目和一个核心，将：1）揭示血管活性背后的潜在机制 与输注HBOC相关的并发症，2）测试HBOC设计的新范例 3）为HBOC设计策略提供蓝图，以控制 血管活性和治疗应用的定制。该计划建立在一个 已经建立的、正在进行的和非常成功的合作努力， 重要的新成果包括：新的高产合成策略的系统大小 基于用聚乙二醇（PEG）进行表面修饰的血红蛋白的增强， 生理学研究表明，某些PEG修饰的依数性 血红蛋白导致血管活性的消除，这是一种新的自动调节模型， 血管活性和一系列生物物理结果，揭示了功能和构象 不同的尺寸增强和诱变策略的结果， 血红蛋白 这个项目由弗里德曼博士担任私家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。该计划项目包括五个项目，和一个生化核心。 项目1（Acharya，AECOM）和项目2（Ho，卡内基梅隆大学）将分别主要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）将重点关注表面修饰和诱变HbS的生物物理和功能表征。项目5（Intaglietta，UCSD）将涵盖HBOC的生理测试。通过项目1和2开发的策略设计的修饰血红蛋白将在蛋白质生物化学核心（Dr. Manjula，AECOM）中生产并进行化学表征，其量为项目2（NMR）、3（光谱学和配体反应性）、4（EPR）和5（生理学）所需。

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).