Modulation of Iron Deposition in SCD and Other Hemoglobinopathies

SCD 和其他血红蛋白病中铁沉积的调节

• 批准号: 7585509
• 负责人: John Brooke Porter
• 金额: $ 33.25万
• 依托单位: CHILDREN'S HOSPITAL & RES CTR AT OAKLAND
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-08-01 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7585509
• 关键词: Accounting; Affect; Age; Anemia; Binding; Biochemical; Biological; Biological Assay; Biological Markers; Bleomycin; Blood; Blood Circulation; Blood Transfusion; Canada; Cardiac; Caring; Cells; Chelation Therapy; Childhood; Chronic; Classification; Control Groups; Cooley' s anemia; Deposition; Diabetic Angiopathies; Diamond-Blackfan anemia; Disease; Employee Strikes; Endocrine; Endocrine Glands; Erythroblasts; Erythroid; Erythropoiesis; Ethnic Origin; Exposure to; Failure; Ferritin; Frequencies; Functional disorder; GDF15 gene; Gender; Grant; Heart; Heart Diseases; Heart failure; Hematology; Hemoglobin; Hemoglobinopathies; Hepatocyte; Homeostasis; Inflammation; Inflammatory; Injury; Interferons; Interleukin-1; Interleukin-1 alpha; Interleukin-10; Interleukin-6; Investigation; Iron; Iron Overload; Longevity; Magnetic Resonance Imaging; Matched Group; Measurement; Measures; Mediating; Mediator of activation protein; Messenger RNA; Methodology; Morbidity - disease rate; Multicenter Studies; Myocardium; Natural History; Normal Range; Organ; Organ failure; Outcome; PLAB Protein; Patients; Pilot Projects; Pituitary Gland; Plasma; Population; Population Control; Population Study; Predisposition; Procedures; Process; Pulmonary Hypertension; Quality Control; Recording of previous events; Recruitment Activity; Regulation; Relative (related person); Reticuloendothelial System; SLC11A2 gene; Serum; Shipping; Ships; Sickle Cell; Sickle Cell Anemia; Source; Specific qualifier value; Stroke prevention; Structure; Syndrome; Techniques; Technology; Testing; Thalassemia; Time; Time Study; Tissues; Transferrin; Transferrin Receptor; Transfusion; absorption; chelation; comparative; cytokine; falls; hepcidin; human TFRC protein; inclusion criteria; inflammatory marker; macrophage; metal transporting protein 1; monocyte; mortality; patient population; population based; prevent; protein expression; public health relevance; response; trafficking; uptake

DESCRIPTION (provided by applicant): In thalassemia major (TM), the complications of transfusional iron (Fe) overload and the benefits of chelation therapy are well defined. In sickle cell disease (SCD), by adulthood, the majority of patients will have received multiple transfusions and it is important that the consequences of transfusional iron overload are clearly defined, as they may differ from those of TM or other forms of transfusional iron overload. In the previous grant cycle, a consortium of expert hematology centers completed a natural history study to compare the frequencies of iron-related organ injury in these two disease populations. Using statistical analyses, the Multi Center Study of Iron Overload (MCSIO) established that endocrinopathies were seen almost exclusively in TM and were related to duration of transfusion. In contrast, cardiac failure was demonstrated with similar frequencies between the two populations; although, using this methodology, it was not possible to differentiate cardiac failure related to iron overload from cardiac failure related to other causes. With the recent introduction of MRI technology that directly quantifies cardiac and pituitary iron, it is now possible to utilize the MCSIO population to determine iron distribution in these heavily transfused populations, determine the biological mechanisms controlling this deposition, and ultimately to examine the relationship of iron overload to organ function. The purpose of this study is, therefore, to undertake systematic comparisons of iron distribution in multi- transfused patients with SCD and other forms of transfusionally-dependent anemias using MRI techniques, to evaluate the functional consequences of such differences, and to explore the mechanisms responsible. In particular, this project will explore the hypothesis that a chronic inflammatory state in SCD leads to hepcidin and cytokine mediated iron withholding within the RES, lower plasma NTBI levels and consequently reduced distribution of iron to the heart and pituitary in SCD, resulting in lower cardiac and endocrine morbidity in this disease. This project includes four specific aims: 1) To compare cardiac and pituitary iron content by MRI in heavily transfused SCD vs TM {or Diamond Blackfan Anemia (DBA)}; 2) To characterize the levels and speciation of NTBI in heavily transfused SCD vs TM (or DBA); 3) To examine mediators of iron trafficking including inflammatory and regulatory cytokines (TNF-a, IL-1, IL-6, IL-10, TGF-¿) and hepcidin in heavily transfused patients with SCD and TM (or DBA); 4) To examine the cellular mechanisms of iron sequestration in the RES in SCD vs TM (or DBA). The study will collaborate with MCSIO Centers to recruit SCD, TM, and DBA patients with similar years of transfusion therapy and age at initiation, complete quantitative MRI to determine heart and pituitary iron overload, and obtain blood under tightly controlled conditions to determine differences in mechanisms important in controlling iron trafficking and storage (including inflammatory cytokines, GDF-15, hepcidin, non-transferrin bound iron, and monocyte/macrophage ferroportin, transferrin receptor and DMT-1 expression). Heart, pituitary and monocyte/macrophage function will be evaluated as a tertiary aim and related to iron parameters. PUBLIC HEALTH RELEVANCE: Despite effective chelation in thalassemia, the patients continue to have cardiac disease, multiple endocrinopathies, and a shortened life span related to iron deposition in target organs. In contrast, SCD patients, even with a similar history of iron exposure, do not show the same levels or frequencies of iron overload in target organs. By comparing iron trafficking mechanisms in these two populations and identifying factors that either limit or exacerbate deposition, it will be possible to develop new therapies that prevent iron deposition from occurring in the heart and endocrine organs, and thereby reduce morbidity and mortality in the thalassemia population.

描述（由申请人提供）： 在Thalassyia Major（TM）中，交叉铁（FE）超负荷的并发症和螯合疗法的益处得到了很好的定义。在成年后，在镰状细胞疾病（SCD）中，大多数患者将接受多次输血，重要的是要明确定义输血铁超负荷的后果，因为它们可能与TM或其他形式的输血铁超载有所不同。在上一个赠款周期中，专家血液学中心的联盟完成了一项自然史研究，以比较这两种疾病人群中与铁相关器官损伤的频率。使用统计分析，铁超载的多中心研究（MCSIO）确定内分泌病几乎完全在TM中看到，与输血持续时间有关。相反，两个人群之间的频率相似，也证明了心力衰竭。但是，使用这种方法，不可能将与铁超负荷有关的心力衰竭与与其他原因相关的心脏衰竭相关的心脏衰竭。随着最近直接量化心脏和垂体铁的MRI技术，现在有可能利用MCSIO种群来确定这些经过翻译的人群中的铁分布，确定控制这种沉积的生物学机制，并最终检查铁超负荷的关系以组织功能。因此，这项研究的目的是使用MRI技术进行多转化的SCD和其他形式的ThruphingProus上来的贫血的患者进行铁分布的系统比较，以评估此类差异的功能后果，并探索负责的机制。特别是，该项目将探讨以下假设：SCD中的慢性炎症状态会导致肝素和细胞因子介导的RES内的铁抗铁，较低的血浆NTBI水平较低，因此在SCD中降低了铁对心脏的分布，导致这种疾病的心脏和内分泌疾病较低。该项目包括四个具体目标：1）在大量翻译的SCD vs TM（或Diamond Blackfan贫血（DBA）}中，MRI比较了心脏和垂体铁的含量； 2）表征大量翻译的SCD与TM（或DBA）中NTBI的水平和规格； 3）检查炎性和调节性细胞因子（TNF-A，IL-1，IL-6，IL-10，TGF-®）和肝素的介体，包括SCD和TM（或DBA）的大量翻译患者中； 4）检查SCD与TM（或DBA）中RES中铁的细胞机制。 The study will collaborate with MCSIO Centers to recruit SCD, TM, and DBA patients with similar years of transfusion therapy and age at initiative, complete quantitative MRI to determine heart and pitutary iron overload, and obtain blood under tightly controlled conditions to determine differences in mechanisms important in controlling iron trafficking and storage (including inflammatory cytokines, GDF-15, hepcidin, non-transferrin bound iron, and单核细胞/巨噬细胞铁托蛋白，转铁蛋白受体和DMT-1表达）。心脏，垂体和单核细胞/巨噬细胞功能将被评估为第三纪，并与铁参数有关。 公共卫生相关性：尽管有有效的地中海贫血螯合，但患者仍患有心脏疾病，多种内分泌病以及与目标器官铁沉积有关的寿命缩短。相比之下，SCD患者即使有类似的铁暴露史，目标器官中铁超载的水平或频率也不相同。通过比较这两个人群中的铁贩运机制以及识别限制或加剧沉积的因素，可以开发新的疗法，以防止铁沉积在心脏和内分泌器官中发生，从而降低地中海贫血人群中的发病率和死亡率。