Pathogenesis and Therapy of Sideroblastic Anemia

描述（由申请人提供）：铁母细胞性贫血的发病机制和治疗：我们最近报道了一种由超氧化物歧化酶2 （SOD2）缺乏引起的新型贫血，与人类铁母细胞性贫血（SA）有着惊人的相似之处。该小鼠模型系统为开展研究提供了一个平台，以更好地了解SA的病理生理基础以及有效治疗这种疾病的作用机制。SA是一种形态学上独特的疾病，其特征是红细胞在发育过程中过量铁的积累。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强调了线粒体作为血红素生物合成，铁运输或发育红细胞铁稳态的位点的重要性。SOD2或锰SOD是一种关键的线粒体内催化抗氧化剂，缺乏这种酶会导致小鼠胚胎晚期或新生儿死亡。对Sod2 - 1幼崽的检查显示线粒体功能障碍的广泛证据，包括肌病、神经病变和代谢紊乱。为了研究SOD2缺乏对细胞的自主影响，我们设计了一种移植系统，利用来自SOD2缺失胚胎的造血干细胞（HSC）重建致命辐照的宿主动物的免疫和造血组织，并发现SOD2缺失导致的主要表型是溶血性贫血。这一结果表明，线粒体功能障碍继发于氧化应激增加，或者红细胞发育过程中关键靶蛋白的直接氧化，可能是SA发病的核心。氧化损伤在这种SA模型中的重要性进一步被一种新型抗氧化剂（催化SOD/过氧化氢酶模拟物）治疗的戏剧性反应所强调。本提案的主要重点是详细表征病理，生物化学和基因表达谱，以确定受SOD2损失影响的关键分子靶点。第二个重点是记录催化抗氧化治疗如何影响这种“发病概况”。本提案的最后一个重点是使用基因表达谱数据来编译一组序列（人类同源物），可用于筛选人类SA病例的RNA。这些研究旨在确定SA中改变的常见分子途径，并将为将来抗氧化剂治疗SA的治疗潜力的临床决策提供重要信息。

DESCRIPTION (provided by applicant): Pathogenesis and Therapy of Sideroblastic Anemia: We have recently reported on a novel munne anemia caused by deficiency of superoxide dismutase 2 (SOD2), that bears striking similarity to human sideroblastic anemia (SA). This murine model system provides a platform from which to conduct studies to better understand both the pathophysiology underlying SA, and the mechanism of action of an effective therapeutic for this condition. 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, or Manganese SOD, is a critical intra-mitochondrial catalytic antioxidant, and deficiency of this enzyme leads to late embryonic or neonatal lethality in mice. Examination of Sod2 -I- pups reveals widespread evidence of 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 hematopoietic 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 antioxidants, catalytic SOD/catalase mimetics. A primary focus of this proposal is detailed characterization of pathology, biochemistry and gene expression profile in order to identify key molecular targets affected by loss of SOD2. A secondary focus is to document how catalytic antioxidant therapy affects this 'pathogenetic profile.' The final focus of this proposal is to use the gene expression profiling data to compile a set of sequences (human homologues) that can be used for screening against RNA from cases of human SA. These studies are designed to identify common molecular pathways that are altered in SA, and will provide crucial information to inform clinical decision making regarding the therapeutic potential of antioxidants as therapy for SA in the future.