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.
