Complications of Hemolysis and Transfusion Therapy

溶血和输血治疗的并发症

基本信息

批准号：
10220124
负责人：
Karina Yazdanbakhsh
金额：
$ 312.15万
依托单位：
NEW YORK BLOOD CENTER
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-20 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10220124
关键词：
Acute Affect Alloimmunization Anemia Anti-Inflammatory Agents B cell differentiation B-Cell Development B-Lymphocytes Babesia Babesiosis Binding Biological Bone Marrow CFU-E Cells Chronic Clinical Collaborations Communication Data Defect Development Disease Disease model Effectiveness Effector Cell Erythroblasts Erythrocyte Transfusion Erythrocytes Erythroid Erythropoiesis Exhibits Exposure to Functional disorder Goals Hematopoietic Hematopoietic stem cells Heme Hemoglobin Hemoglobinopathies Hemolysis Hemolytic Anemia Human Immune Immune response Impairment In Vitro Infection Infectious Agent Inflammation Inflammatory Innate Immune Response Iron Island Knowledge Life Lung Mediator of activation protein Mesenchymal Stem Cells Metabolic Metabolic Pathway Methods Molecular Monitor Mus Outcome Output Oxidative Stress Pathway interactions Patients Phenotype Play Prevention Productivity Protocols documentation Quinine Reaction Regulation Research Project Grants Risk Role Sampling Seminal Sickle Cell Sickle Cell Anemia Signal Transduction Sputum T-Lymphocyte T-Lymphocyte Subsets Testing Transfusion Transplantation Viscosity acute chest syndrome base cell type clinical application extracellular vesicles heme 1 human subject in vivo Model infection rate inflammatory milieu insight iron metabolism macrophage metabolome mouse model multidisciplinary patient population prevent progenitor programs response sickling small molecule synergism targeted agent uptake vascular endothelial dysfunction

项目摘要

Overall Abstract Our Program Project focuses on mechanistic understanding of the beneficial and harmful effects of red blood cell (RBC) transfusions in patients with hemoglobinopathies. Increasing evidence suggest that free hemoglobin and heme play central roles in many aspects of the pathophysiology of hemolytic anemias, especially in SCD, causing vascular endothelial dysfunction, inflammation, and oxidative stress. Our Team has shown that innate and key humoral immune cells and hematopoietic niche cells are sensitive to the effects hemolysis and that heme-sensing mechanisms are key to the response to transfusions. The overall working hypothesis of this PPG is that heme overload leads to altered immune system response and a dysregulated bone marrow niche. We further posit that effectiveness of transfusions in hemolytic disorders depends on their ability to switch the proinflammatory to an anti-inflammatory environment. Building on highly inter-related and synergistic research projects led by a group of multidisciplinary local experts, including a highly promising ESI, we will interrogate the impact of hemolysis and outcome of transfusions on complications associated with SCD, ranging from alloimmunization (Project 1) and infections of hemoparasites (Project 2) to ACS (Project 3) and potentially affecting hematopoietic transplant outcomes (Project 4). Specifically, we will probe heme pathways specifically in B and T cells during transfusions to test the hypothesis that hemolysis directly affects humoral immune response to transfusions and that altered DOCK8/ROS/HO-1 heme pathways dictate alloimmunization risk and even bystander hemolysis associated with life-threatening delayed hemolytic transfusion reactions (Project 1). We will examine mechanisms of bystander hemolysis in hemoparasite infections and test the hypothesis that the switch from anti- to proinflammatory states in response to hemolysis and exacerbation of dysregulated erythropoiesis may underlie the exaggerated hyperhemolytic state (Project 2). Building on our data on modulation of innate immune response by hemolysis, we will determine the relevance of heme-induced inflammatory macrophage in the development of the debilitating sickle acute chest syndrome and whether transfusion outcomes are dependent on an anti-inflammatory metabolic switch in macrophages (Project 3). We will also test the hypothesis that the proinflammatory effects of free heme leads to dysfunction of the bone marrow hematopoietic niche and hematopoietic stem/progenitor cells, which can be alleviated by transfusions (Project 4). An Administrative Core will facilitate communication and integrate scientific goals and assure that high scientific productivity standards are maintained. The Human Subject Core will provide clinically annotated biological samples as well as clinically based insights to facilitate and enhance the clinical applicability of the findings emerging from this Program Project. We believe that the proposed Projects are highly interactive and that advances developed within each will have great value to other Projects. We further believe that through a PPG mechanism our Program will achieve a comprehensive mechanistic understanding how transfusions impact key heme pathways in hemoglobinopathies will provide the necessary framework for optimization of transfusion management and support for these highly vulnerable patient population.

总体抽象我们的计划项目着重于对红血的有益和有害影响的机械理解血红蛋白病患者的细胞（RBC）输血。越来越多的证据表明自由血红蛋白血红素在溶血性贫血的病理生理学的许多方面起着核心作用，尤其是在SCD中引起血管内皮功能障碍，炎症和氧化应激。我们的团队表明了天生关键的体液免疫细胞和造血细胞细胞对溶血的影响敏感，并且血红素感应机制是对输血反应的关键。该PPG的总体工作假设是血红素过载导致免疫系统反应改变和失调的骨髓小裂。我们进一步认为，输血在溶血疾病中的有效性取决于其切换的能力促进抗炎环境的炎症。建立在高度相关和协同研究的基础上由一群跨学科的本地专家领导的项目，包括高度有前途的ESI，我们将审问溶血和输血结果对与SCD相关的并发症的影响，从同种免疫（项目1）和造血（项目2）的感染（项目3）（项目3）及其潜在的影响造血移植结果（项目4）。具体而言，我们将专门探测血红素途径在输血过程中B和T细胞中，测试溶血直接影响体液免疫的假设对输血的反应，改变了Dock8/ros/ho-1血红素途径决定了同种免疫的风险和甚至旁观者溶血也与威胁生命的延迟溶血输血反应有关（项目1）。我们将检查肢体寄生虫感染中旁观者溶血的机制，并检验以下假设。响应溶血和失调的恶化，从抗炎状态转向促炎状态红细胞生成可能是夸张的过度溶血状态的基础（项目2）。以我们的数据为基础通过溶血调节先天免疫反应，我们将确定血红素诱导的相关性炎症性巨噬细胞在使镰状急性胸部综合征的发展中输血结果取决于巨噬细胞中的抗炎代谢开关（项目3）。我们还将检验以下假设：游离血红素的促炎作用导致骨髓功能障碍造血生态位和造血茎/祖细胞，可以通过输血来缓解（项目 4）。行政核心将促进沟通并整合科学目标，并确保高保持科学生产力标准。人类主题核心将提供临床注释生物样品以及基于临床的见解，以促进和增强从这个程序项目中出现的发现。我们认为，拟议的项目具有高度互动性，并且每个项目内发展的进步将对其他项目具有巨大的价值。我们进一步相信，通过 PPG机制我们的计划将实现全面的机械理解，了解输血的影响如何血红蛋白病中的关键血红素途径将为优化输血提供必要的框架管理和支持这些高度脆弱的患者人群。