Pathogenesis and Therapy of Sideroblastic Anemia

摘要：铁粒幼细胞性贫血的发病机制和治疗：我们最近报道了一种新的小鼠贫血引起的超氧化物歧化酶2（SOD 2）的缺乏，承担惊人的相似性，人类铁粒幼细胞性贫血（SA）。SA是一组形态学上不同的疾病，其特征在于发育期间红细胞内过量铁的积累。最近已经阐明了几种SA亚型的遗传病变，并且在每种情况下都突出了线粒体作为血红素生物合成、铁转运或铁稳态在红细胞发育中的位点的重要性。SOD 2是一种关键的线粒体内催化剂/氧化剂，这种酶的缺乏导致小鼠的晚期胚胎或新生儿死亡，病理学证据表明广泛的线粒体功能障碍，包括肌病、神经病和代谢紊乱。为了研究SOD 2的细胞自主效应， 由于缺乏SOD 2，我们设计了一种移植系统，其中来自SOD 2缺失胚胎的造血干细胞（HSC）用于重建致死辐射的宿主动物的免疫和造血组织，并发现由SOD 2缺失导致的主要表型是溶血性贫血。这一结果表明，继发于氧化应激增加的线粒体功能障碍，或者可能是红细胞发育过程中关键靶蛋白的直接氧化，可能是SA发病机制的核心。氧化损伤在SA模型中的重要性通过对新型抗氧化剂/氧化剂、催化SOD/过氧化氢酶模拟物治疗的显著反应而进一步突出。本提案的一个主要重点是详细 本发明的目的在于鉴定病理学、生物化学和蛋白质/基因表达谱的特征，以鉴定受SOD 2损失影响的关键分子靶标。第二个重点是记录催化剂/氧化剂治疗如何影响这种“发病特征”。同时，我们将检查SA患者骨髓红系祖细胞的基因表达谱，部分是为了对这种异质性疾病进行分类，部分是为了寻找与SOD 2缺乏症的重叠。这些研究将有助于阐明氧化应激增加是否是SA的一个特征，从而为抗/氧化剂作为治疗这种疾病的潜在作用提供指导。本研究过程中开发的技术--蛋白质氧化的评价和氧化蛋白质的纯化方法--将为回答更普遍的问题提供工具 关于蛋白质氧化在其他类型的溶血过程中的作用，以及作为正常红细胞存活的决定因素。

Abstract: Pathoqenesis and Therapy of Sideroblastic Anemia: We have recently reported on a novel murine anemia caused by deficiency of superoxide dismutase 2 (SOD2), that bears striking similarity to human sideroblastic anemia (SA). SA is a morphologically distinct group of disorders characterized by accumulation of excess iron within red cells during development. Genetic lesions responsible for several subtypes of SA have been recently elucidated, and in each case highlight the importance of mitochondria as a locus for heme biosynthesis, iron transport or iron homeostasis in developing red blood cells. SOD2, is a critical intra-mitochondrial catalytic ant/oxidant, and deficiency of this enzyme leads to late embryonic or neonatal lethality in mice, with pathologic evidence of widespread mitochondrial dysfunction including myopathy, neuropathy and metabolic derangement. In order to study cell-autonomous effects of SOD2 deficiency, we devised a transplantation system in which hematopeietic stem cells (HSC) from Sod2 null embryos were used to reconstitute the immune and hematopoietic tissues of lethally irradiated host animals, and found that a major phenotype resulting from loss of SOD2 is a hemolytic anemia. This result suggested that mitochondrial dysfunction secondary to increased oxidative stress, or perhaps direct oxidation of key target proteins during red cell development, may be central to the pathogenesis of SA. The importance of oxidative damage in this model of SA was further highlighted by the dramatic response to therapy with a novel class of ant/oxidants, catalytic SOD/catalase mimetics. A primary focus of this proposal is detailed characterization of pathology, biochemistry and protein/gene expression profiles in order to identify key molecular targets affected by loss of SOD2. A secondary focus is to document how catalytic ant/oxidant therapy affects this 'pathogenetic profile.' In parallel, we will examine gene expression profiles from marrow erythroid progenitors of SA patients, in part to classify this heterogeneous disorder, and in part to look for overlap with SOD2 deficiency. These studies will help to elucidate whether increased oxidative stress is a characteristic of SA, and thereby provide guidance as to the potential role of ant/oxidants as therapy for this disorder. The techniques developed in the course of this study--evaluation of protein oxidation and methods for purification of oxidized proteins--will provide tools for answering more general questions regarding the role of protein oxidation in other types of hemolytic processes, and as a determinant of survival of normal erythrocytes.