Sandler S, Andersson A K, Barbu A, Hellerström C, Holstad M, Karlsson E, Sandberg J O, Strandell E, Saldeen J, Sternesjö J, Tillmar L, Eizirik D L, Flodström M, Welsh N
Department of Medical Cell Biology, Uppsala University, Sweden.
Ups J Med Sci. 2000;105(2):17-34. doi: 10.1517/03009734000000053.
Type 1 diabetes is an autoimmune disease leading to extensive destruction of the pancreatic beta-cells. Our research focusses on the role of beta-cells during the course of the disease, aiming at finding novel strategies to enhance beta-cell resistance against the cytotoxic damage inflicted by the immune system. Special attention has been paid to the possibility that cytokines released by the immune cells infiltrating the pancreatic islets can directly suppress and kill beta-cells. Certain cytokines (interleukin-1beta, tumor necrosis factor-alpha and interferon-gamma) either alone or in combination, are able to activate signal transduction pathways in beta-cells leading to transcription factor activation and de novo gene expression. In this context, it has been found that induction of inducible nitric oxide synthase mediates an elevated production of nitric oxide, which impairs mitochondrial function and causes DNA damage eventually leading to apoptosis and necrosis. However, other induced proteins SUCH AS heat shock protein 70 and superoxide dismutase may reflect a defense reaction elicited in the beta-cells by the cytokines. Our strategy is to further seek for proteins involved in both destruction and protection of beta-cells. Based on this knowledge, we plan to apply gene therapeutic approaches to increase expression of protective genes in beta-cells. If this is feasible we will then evaluate the function and survival of such modified beta-cells in animal models of type 1 diabetes such as the NOD mouse. The long-term goal for this research line is to find novel approaches to influence beta-cell resistance in humans at risk of developing type 1 diabetes.
1型糖尿病是一种自身免疫性疾病，会导致胰腺β细胞广泛受损。我们的研究聚焦于β细胞在疾病过程中的作用，旨在寻找新策略来增强β细胞抵抗免疫系统造成的细胞毒性损伤的能力。我们特别关注浸润胰岛的免疫细胞释放的细胞因子直接抑制和杀死β细胞的可能性。某些细胞因子（白细胞介素-1β、肿瘤坏死因子-α和干扰素-γ）单独或联合使用，能够激活β细胞中的信号转导通路，导致转录因子激活和新基因表达。在这种情况下，已发现诱导型一氧化氮合酶的诱导介导一氧化氮产量升高，这会损害线粒体功能并导致DNA损伤，最终导致细胞凋亡和坏死。然而，其他诱导蛋白，如热休克蛋白70和超氧化物歧化酶，可能反映了细胞因子在β细胞中引发的防御反应。我们的策略是进一步寻找参与β细胞破坏和保护的蛋白质。基于这一认识，我们计划应用基因治疗方法来增加β细胞中保护基因的表达。如果可行，我们将在1型糖尿病动物模型（如非肥胖糖尿病小鼠）中评估此类修饰β细胞的功能和存活情况。这条研究路线的长期目标是找到新方法来影响有患1型糖尿病风险的人类的β细胞抵抗能力。
