MECHANISMS OF SUSCEPTIBILITY TO ALLOXAN IN MICE

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Free radicals are reactive oxygen species that are especially damaging to pancreatic Beta-cell They are generated within Beta-cell They are generated within Beta-cells by the combination of cytokines secreted by leukocytes comprising the insulitic infiltrate during development of insulin dependent diabetes (IDDM). Destructive oxygen free radicals are generated in Beta-cells after exposure to environmental toxins, such as alloxan (AL). Al, resembling the glucose molecule, is selectively taken up rodent Beta-cell wherein it decomposes to produce highly toxic oxygen free radicals. Beta-cells have weaker defenses to oxidative damage than do cells from other tissues. Unknown whether or not genes expressed in B-cells can contribute to the overall make-up of an individual is genetically susceptible or resistant to Beta-cell loss. The goal of this fellowship proposal is to address this question using two inbred strains of mice selected for alloxan susceptibility (ALS) versus (ALR) IDDM induction. The basis for this differential in alloxan susceptibility is apparently the ability of the ALR strain to ~defuse~ the alloxan-generated free radical stress. The same pattern of susceptibility/resistance holds for treatment with streptozotocin, another Beta cell toxin. Biochemical analyze will test whether the strains different in systemic and/or islet defenses to the reactive oxygen species generate AL. Genetic segregation analysis will elucidate the gene or genes controlling differential susceptibility. Finally, Islets in vitro will be tested for ability to resist free radical mediated stress induced by combinations of cytotoxic cytokines. The elucidation of the genetic basis for the heightened resistance to Beta cell toxins should have practical applications in therapies for IDDM, including islet transplantation.