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Complications of Hemolysis and Transfusion Therapy

溶血和输血治疗的并发症

基本信息

批准号：
10023587
负责人：
Karina Yazdanbakhsh
金额：
$ 314.25万
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/10023587
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 Immune system Impairment In Vitro Infection Infectious Agent Inflammation Inflammatory Innate Immune Response Iron Island Knowledge Life Lung Macrophage Activation 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.

整体的抽象