MECHANISMS OF SUSCEPTIBILITY TO ALLOXAN IN MICE

自由基是活性氧物质， 破坏胰腺β细胞它们在β细胞内产生 它们在β细胞内通过细胞因子的组合产生 由白细胞分泌，包括胰岛浸润， 胰岛素依赖性糖尿病（IDDM）的发展。 破坏性氧 暴露于以下物质后，β细胞中产生自由基： 环境毒素，如四氧嘧啶（AL）。 艾尔，就像 葡萄糖分子被啮齿动物β细胞选择性摄取，其中它 分解产生剧毒的氧自由基。 β细胞 对氧化损伤的防御能力比其他来源的细胞弱 组织中 尚不清楚B细胞中表达的基因是否可以 决定一个人整体构成的因素是基因 对β细胞损失敏感或有抵抗力。 这个目标 研究金的建议是解决这个问题，使用两个近亲繁殖的 选择用于四氧嘧啶敏感性（ALS）的小鼠品系与 (ALR)胰岛素依赖型糖尿病诱导。 四氧嘧啶中这种差异的基础 敏感性显然是ALR菌株的能力， ~缓和~四氧嘧啶产生的自由基应激。 相同的模式 敏感性/耐药性对于链脲佐菌素治疗保持不变， 另一种贝塔细胞毒素 生化分析仪将检测 在系统和/或胰岛对反应性抗体的防御方面不同的菌株 氧物种产生AL。遗传分离分析将 阐明控制不同易感性的基因。 最后，将测试体外胰岛抵抗游离 细胞毒性和细胞毒的组合诱导的自由基介导的应激 细胞因子 阐明了高血压的遗传基础， 对β细胞毒素的抗性应该有实际应用， 胰岛素依赖型糖尿病的治疗，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.