Kinetics of Red Blood Cell Clearance in Chronically Transfused Children with Sickle Cell Disease

慢性输血镰状细胞病儿童红细胞清除动力学

• 批准号: 9977409
• 负责人: Marianne Elaine McPherson Yee
• 金额: $ 17.11万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-03 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9977409
• 关键词: Adherence; Adolescent; Adult; Adverse event; Aliquot; Alloimmunization; Appearance; Benchmarking; Biotin; Biotinylation; Blood Circulation; Blood Transfusion; Blood specimen; Cell Aging; Cell Surface Proteins; Cell Survival; Cell Therapy; Cerebral Ischemia; Characteristics; Child; Childhood; Chronic; Clinical; Clinical Research; Clinical Trials; Disease; Donor Selection; Early identification; Enrollment; Erythrocyte Transfusion; Erythrocytes; Erythropoiesis; Failure; Future; Glucosephosphate Dehydrogenase; Glucosephosphate Dehydrogenase Deficiency; Goals; Hematology; Hemoglobin; Hemoglobin A; Hemoglobin SS; Hemoglobin concentration result; Hemolysis; Hour; Immune; Immune system; Immunologics; Individual; Intervention; Kinetics; Knowledge; Label; Learning; Master' s Degree; Measures; Mediating; Membrane; Mentorship; Metabolic; Modeling; Morbidity - disease rate; Outcome; Patient Selection; Patient-Focused Outcomes; Patients; Pattern; Pediatric Hematologist; Pilot Projects; Population; Production; Prophylactic treatment; Prospective Studies; Recording of previous events; Recovery; Regimen; Research Personnel; Reticulocytes; Reticuloendothelial System; Risk Factors; Role; Sampling; Sickle Cell; Sickle Cell Anemia; Specific qualifier value; Spleen; Splenomegaly; Stroke; Stroke prevention; Surface; Time; Toxic effect; Transfusion; Variant; acute stroke; base; career; clinical efficacy; cohort; effective therapy; experience; improved; improved outcome; in vivo; individual patient; interpatient variability; longitudinal analysis; metabolomics; patient oriented research; personalized approach; precision medicine; prospective; response; senescence; stroke event; stroke risk; transfusion medicine; treatment response

Project Summary Sickle cell disease (SCD) carries significant morbidity as a result of red blood cell (RBC) sickling and hemolysis. Stroke is one of the most devastating sequelae of SCD. Chronic transfusion therapy (CTT) reduces stroke risk by (1) supplying normal, non-sickle RBC to circulation, thereby reducing the percentage of endogenous sickle RBC in circulation, and (2) maintaining a higher hemoglobin (Hb), thereby suppressing erythropoiesis of new sickle RBC. While the efficacy of CTT in stroke prophylaxis is well-established, nearly 45% of children continue to have silent or overt strokes despite CTT. The failure of CTT to prevent stroke events may be related to inadequate reduction of circulating sickle RBC and erythropoiesis. The amount of circulating sickle-RBC is related to the survival kinetics of both transfused RBC and endogenous sickle RBC. In a large, longitudinal analysis of CTT in SCD, we found wide variation in the survival of donor RBC following transfusion, with faster clearance associated with patient immune features (historical RBC alloimmunization and spleen presence) and with donor RBC glucose-6-phosphate-dehydrogenase (G6PD) deficiency. To better understand the roles of patient and donor factors in the survival and clearance of transfused RBC, we propose a mechanistic, clinical trial during chronic transfusion episodes in patients with SCD, in which a small aliquot of each transfused unit is labeled with biotin conjugated to RBC surface proteins, to safely identify and measure the in vivo survival of donor RBC. Aim 1 will examine the relationships of the recipient’s immune system (past alloimmunization, splenic volume, and markers of reticuloendothelial system function) on the post-transfusion survival of biotin-labeled donor RBC. Aim 2 will examine the relationships of donor RBC G6PD levels and donor RBC metabolomics with the in vivo survival and changes in donor RBC senescence markers. Completion of these aims will increase our understanding of mechanisms for the variability in RBC survival during CTT, identifying donor and recipient risk factors for decreased RBC survival. Ultimately this knowledge will inform the management of CTT to improve the prevention of strokes in SCD. The applicant, Dr. Yee, is a pediatric hematologist and an emerging clinical researcher in SCD, with a master’s degree in clinical research and experience with pilot and prospective studies of patient-oriented research in SCD. Dr. Yee has identified an exceptional mentorship team with expertise in RBC survival studies and biotinylation, donor RBC metabolomics, and clinical research in SCD. The candidate's short-term career goals for this K23 application are to 1) Develop formal expertise in transfusion medicine; 2) Expand expertise in conducting prospective, interventional clinical research in pediatric SCD and transfusion medicine; 3) Learn the use and interpretation of biotinylation of RBC transfusion to study transfusion survival in vivo. The candidate's long-term career goals are to improve transfusion and cellular therapies with a personalized approach to blood transfusion in children and adults with SCD and to improve the clinical outcomes of transfusion and other SCD therapies while decreasing toxicity and adverse events.

项目摘要 镰状细胞病（SCD）由于红细胞（RBC）疾病而带来明显的发病率 溶血。中风是SCD最具破坏性的后遗症之一。慢性输血疗法（CTT）减少 中风风险（1）提供正常的，非弹RBC的流通，从而降低了百分比 内源性镰状RBC流通中，（2）保持较高的血红蛋白（HB），从而抑制 新镰状RBC的红细胞生成。虽然CTT在预防中风方面的效率是完善的，但几乎 有45％的儿童继续保持沉默或公开的目的地CTT。 CTT无法防止中风 事件可能与减少循环镰状RBC和红细胞生成的减少有关。数量 循环镰状-RBC与输血的RBC和内源性镰刀RBC的生存动力学有关。在 SCD中CTT的纵向分析，我们发现供体RBC生存的差异很大 输血，具有与患者免疫特征相关的更快间隙（历史RBC AlloMunision 和脾存在）以及供体RBC葡萄糖-6-磷酸二氢酶（G6PD）缺乏症。更好 了解患者和供体因素在输血RBC的生存和清除率中的作用，我们提出 SCD患者的慢性输血发作期间的机械临床试验，其中一小部分的等分试样 每个输血单元都用结合与RBC表面蛋白的生物素标记，以安全识别和测量 供体RBC的体内生存。 AIM 1将检查接收者免疫系统的关系（过去 在转移后灌注上的网状内皮系统功能的同种异体免疫，脾气和标记 生物素标记的供体RBC的存活率。 AIM 2将检查供体RBC G6PD级别的关系和 供体RBC代谢组学具有体内存活和供体RBC感应标记的变化。 这些目标的完成将增加我们对RBC生存变异性机制的理解 在CTT期间，确定改善RBC存活的供体和受体风险因素。最终这些知识 将告知管理CTT的管理，以改善SCD中风的预防。申请人Yee博士是 SCD的儿科血液学家和新兴临床研究人员，拥有临床研究硕士学位 以及在SCD中对以患者为导向的研究进行试验和前瞻性研究的经验。 Yee博士已经确定 捐助者RBC一个具有RBC生存研究和生物素化专业知识的杰出精神团队 代谢组学和SCD的临床研究。候选人在此K23申请中的短期职业目标 到1）在输血医学方面发展正式专业知识； 2）扩大实行前景方面的专业知识， 小儿SCD和输血医学的介入临床研究； 3）学习使用和解释 RBC输血的生物素化研究在体内研究输血生存。候选人的长期职业目标 用个性化的儿童输血方法来改善输血和细胞疗法 以及患有SCD的成年人，并改善输血和其他SCD疗法的临床结果 降低毒性和不良事件。