MECHANISMS OF SUSCEPTIBILITY TO ALLOXAN IN MICE

自由基是一种活性氧物种，尤其是 它们在胰岛β细胞内产生对胰岛β细胞的损伤作用 它们是在β细胞内通过细胞因子的结合而产生的 由白细胞分泌，其中包括胰岛素浸润液 发展为胰岛素依赖型糖尿病(IDDM)。破坏性氧 暴露于空气中的β细胞会产生自由基 环境毒素，如四氧嘧啶(AL)。Al，类似于 葡萄糖分子，选择性地被啮齿动物的β细胞摄取，其中 分解产生剧毒的氧自由基。胰岛β细胞 对氧化损伤的防御能力比其他来源的细胞更弱 纸巾。B细胞中表达的基因是否可以 对个人整体构成有贡献的是遗传因素 对β细胞丢失敏感的或抵抗的。这样做的目的是 团契的提议是用两个近交系来解决这个问题 四氧嘧啶敏感性(ALS)小鼠品系与 (ALR)IDDM诱导。四氧嘧啶中这种差异的基础 敏感度显然是ALR菌株对 化解~四氧嘧啶产生的自由基应激。同样的模式 对链脲佐菌素治疗的敏感性/耐药性， 另一种贝塔细胞毒素。生化分析将测试是否 对反应性的系统和/或胰岛防御能力不同的菌株 氧物种产生铝。基因分离分析将 阐明控制差异易感性的一个或多个基因。 最后，将测试体外培养的胰岛抵抗游离的能力。 细胞毒联合作用诱导的自由基介导的应激反应 细胞因子。高血压病的遗传学基础的阐明 对Beta细胞毒素的抗药性应该在 IDDM的治疗，包括胰岛移植。

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.