Beta-cell responses to oxidative stress and Type 1 diabetes

1型糖尿病（T1 D）是一种自身免疫性疾病，由于产生活性氧（ROS）、促炎细胞因子/趋化因子和T细胞效应分子，导致胰腺β细胞破坏。最近的证据表明，β细胞功能障碍也是T1 D发病机制的激活参与者。我们将比较T1 D易感非肥胖糖尿病（NOD）小鼠与T1 D耐药NOD.Ncf1m1J小鼠发生的胰腺β细胞功能特性变化，这些小鼠无法产生NADPH氧化酶（NOX）衍生的超氧化物。我们将研究NOD.Ncf1m1J小鼠中ROS的缺乏如何调节β细胞的功能特性，与免疫细胞的相互作用以及T1 D的延迟。为了证实我们的遗传小鼠模型，我们将检查用药理学锰金属卟啉抗氧化剂治疗人类胰岛后胰腺b细胞的反应。我们的总体假设是ROS的减少将保留或增强β细胞功能特性，如通过T1 D易感NOD小鼠和人胰岛中的转录特征和胰岛素分泌所定义的。为了解决这一假设，将定义以下独立和相互关联的目标：（1）定义ROS的遗传消融如何保留β细胞功能特性。(2)确定ROS的缺乏是否可以降低胰腺β细胞介导的炎症反应。(3)确定抗氧化剂治疗是否保留小鼠和人类β细胞的功能。从我们的研究中获得的见解将增加我们对糖尿病病因学的理解，也可能指向未来采用抗氧化化合物来保护和/或替代胰腺β细胞功能的策略。

Type 1 diabetes (T1D) is an autoimmune disease resulting in pancreatic β-cell destruction due to the generation of reactive oxygen species (ROS), proinflammatory cytokines/chemokines, and T cell effector molecules. Recent evidence has shown that β-cell dysfunction is also an activate participant in T1D pathogenesis. We will compare pancreatic β-cell functional identity changes that occur with T1D-prone Non-obese Diabetic (NOD) mice with T1D-resistant NOD.Ncf1m1J mice unable to generate NADPH oxidase (NOX)-derived superoxide. We will examine how the absence of ROS in NOD.Ncf1m1J mice can regulate β-cell functional identity, interactions with immune cells, and delay in T1D. To corroborate our genetic mouse models, we will examine pancreatic b-cell responses following treatment with a pharmacological manganese metalloporphyrin antioxidant with human islets. Our overarching hypothesis is that reduction of ROS will preserve or enhance β-cell functional identity, as defined by transcriptional signatures and insulin secretion in T1D-prone NOD mice and human islets. To address this hypothesis, the following independent and interrelated aims will be defined: (1) Define how genetic ablation of ROS preserves β-cell functional identity. (2) Determine whether the absence of ROS can decrease pancreatic β-cell-mediated inflammatory responses. (3) Determine whether antioxidant treatment preserves the function of mouse and human β-cells. The insights gained from our studies will increase our understanding of diabetes etiology and may also point to future strategies employing antioxidant compounds to preserve and/or replace the function of pancreatic β-cells.