Modulation of erythrocyte function by complement

补体对红细胞功能的调节

基本信息

批准号：
8631096
负责人：
IONITA Calin GHIRAN
金额：
$ 42.63万
依托单位：
BETH ISRAEL DEACONESS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-05-01 至 2016-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8631096
关键词：
Address Adherence Antigen-Antibody Complex Attenuated Autocrine Communication Autoimmune Diseases Binding Biochemical Blood Blood Circulation Blood capillaries Cell membrane Cell physiology Cells Cellular biology Cessation of life Complement Complement 3b Complement 4b Complement Activation Complement Receptor Data Deposition Development Distress Endothelial Cells Environment Erythrocytes Event Excision Feedback Gases Generations Glycophorin A Goals Homeostasis Human Image Immune Immune response In Vitro Infection Inflammatory Injury Intercept Ligation Liver Malaria Mediating Membrane Microbe Microcirculation Microscopy Morbidity - disease rate Organ Oxygen Pathology Patients Perfusion Phenotype Physiological Primates Purinoceptor Role Sepsis Septic Shock Sickle Cell Anemia Signal Pathway Signal Transduction Spleen System Therapeutic Tissues Trauma Video Microscopy Work autocrine base capillary clinically relevant cost density design effective therapy immune clearance improved in vivo in vivo imaging innovation macrophage mortality multiorgan injury neutrophil novel novel therapeutics paracrine particle prevent public health relevance response septic therapeutic target

项目摘要

DESCRIPTION (provided by applicant): Excessive complement activation is associated with a wide spectrum of pathologies including malaria, sickle cell disease, autoimmune diseases, trauma injury, and sepsis. In the U.S., sepsis alone is responsible for over 210,000 deaths each year, with associated costs estimated at over $16.7 billion. Our current understanding of sepsis is that complement-mediated host immune responses to infection are responsible for microcirculatory distress and severe organ damage. Red blood cells (RBCs) have critical, non- redundant roles in maintaining a non-inflammatory intravascular environment by capturing complement- opsonized particles through complement receptor 1 (CR1) and delivering them to macrophages in the liver and spleen. We have found that during excessive complement activation the additional engagement of glycophorin A (GPA) by soluble complement fragments significantly inhibits RBC membrane deformability and promotes RBC ATP release. Our new data challenge the classic paradigm of RBCs as singularly non-inflammatory cells, revealing that during excessive complement activation, RBCs cease to maintain a non-inflammatory environment and actively promote a pro-inflammatory intravascular milieu. Mechanisms responsible for changing RBCs into proinflammatory cells have not been known. A better understanding of the "reprogramming" of RBCs into proinflammatory cells will allow the development of novel, effective therapies for septic patients. The long-term objective of this work is to understand the contribution of RBCs and complement to tissue and organ damage during sepsis. Our overall hypothesis is that during excessive complement activation, engagement of GPA by excess complement fragments reprograms RBCs into pro- inflammatory cells through a critical ATP-dependent autocrine signaling mechanism. The overall objective of our proposal is to determine the mechanisms by which engagement of GPA by complement fragments promote ATP release and inhibit RBC functions. The rational for these studies is that we have revealed a unique and crucial purinergic requirement for the GPA-mediated detrimental effect of complement on RBC functions, which suggests that RBC-generated ATP, through autocrine and paracrine purinergic mechanisms, promotes and maintains an inflammatory intravascular milieu. The innovation of our studies is that we have discovered a novel facet of RBC-complement interaction that may considerably impact the efficacy and design of targeted therapeutic approaches that will significantly lower the morbidity and mortality of sepsis. Our studies will have a significant impact on our understanding of the potential of RBCs and purinergic signaling as novel targets for therapy in pathological situation associated with excessive complement activation, as well as on our basic understanding of RBC biology in normal and pathological situations.

描述（由申请人提供）：补体过度激活与多种病理学相关，包括疟疾、镰状细胞病、自身免疫性疾病、创伤性损伤和败血症。在美国，每年仅败血症就导致超过 21 万人死亡，相关费用估计超过 167 亿美元。我们目前对脓毒症的理解是，补体介导的宿主对感染的免疫反应是导致微循环窘迫和严重器官损伤的原因。红细胞 (RBC) 通过补体受体 1 (CR1) 捕获补体调理颗粒并将其递送至肝脏和脾脏中的巨噬细胞，从而在维持非炎症性血管内环境方面发挥着关键的、非冗余的作用。我们发现，在补体过度激活期间，可溶性补体片段与血型糖蛋白 A (GPA) 的额外结合显着抑制红细胞膜变形性并促进红细胞 ATP 释放。我们的新数据挑战了红细胞作为单一非炎症细胞的经典范例，揭示了在补体过度激活期间，红细胞停止维持非炎症环境并积极促进促炎性血管内环境。将红细胞转变为促炎细胞的机制尚不清楚。更好地了解红细胞“重编程”为促炎细胞将有助于为脓毒症患者开发新颖、有效的疗法。这项工作的长期目标是了解红细胞和补体对脓毒症期间组织和器官损伤的贡献。我们的总体假设是，在补体过度激活期间，过量补体片段与 GPA 的结合，通过关键的 ATP 依赖性自分泌信号机制将红细胞重新编程为促炎细胞。我们提案的总体目标是确定补体片段与 GPA 的结合促进 ATP 释放和抑制红细胞功能的机制。这些研究的理由是，我们已经揭示了 GPA 介导的补体对红细胞功能的有害影响的独特且关键的嘌呤能要求，这表明红细胞产生的 ATP 通过自分泌和旁分泌嘌呤能机制，促进和维持血管内炎症环境。我们研究的创新之处在于，我们发现了红细胞-补体相互作用的一个新方面，它可能会极大地影响靶向治疗方法的功效和设计，从而显着降低脓毒症的发病率和死亡率。我们的研究将对我们对红细胞和嘌呤信号传导作为与补体过度激活相关的病理情况下的新治疗靶点的潜力的理解产生重大影响，并对我们对正常和病理情况下红细胞生物学的基本理解产生重大影响。

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Ligation of Glycophorin A Generates Reactive Oxygen Species Leading to Decreased Red Blood Cell Function.

DOI：
10.1371/journal.pone.0141206
发表时间：
2016
期刊：
PloS one
影响因子：
3.7
作者：
Khoory J;Estanislau J;Elkhal A;Lazaar A;Melhorn MI;Brodsky A;Illigens B;Hamachi I;Kurishita Y;Ivanov AR;Shevkoplyas S;Shapiro NI;Ghiran IC
通讯作者：
Ghiran IC

CR1-mediated ATP Release by Human Red Blood Cells Promotes CR1 Clustering and Modulates the Immune Transfer Process