A novel target for type 1 diabetes

1型糖尿病（T1 D）是一种自身免疫性疾病，其由胰岛素产生的永久性破坏引起。 通过自我攻击的免疫细胞来破坏胰腺中的β细胞。这些自我攻击的免疫T细胞 一般在开发阶段消除，如果发生任何泄漏，应在外围容忍。 因此，T细胞耐受性的诱导/维持失败对于T1 D至关重要。然而，分子 诱导/维持T细胞耐受性的机制在很大程度上仍然未知。在这里我们发现 Sirt 1功能的丧失会导致异常升高的免疫反应和外周免疫系统的破坏。 T细胞的耐受性因此，Sirt 1-/-小鼠产生自发性自身免疫。这些结果 表明Sirt 1是T细胞活化负调节因子，是维持T细胞耐受性所必需的。是 因此，没有Sirt 1的小鼠可能发展为T1 D。Sirt 1被小分子激活， 白藜芦醇可以通过抑制β细胞攻击自身免疫T细胞来潜在地用于治疗T1 D。的确， 我们实验室的初步研究结果表明，Sirt 1的激活剂白藜芦醇保护NOD小鼠， 从T1 D 因此，该建议旨在确定Sirt 1如何发挥作用的分子机制， T细胞的无能因子，并研究Sirt 1功能失调如何参与T细胞的发展， T1D我们还将进一步确定白藜芦醇对T1 D的预防/治疗作用。 我们提出的研究结果可能揭示T细胞耐受性的新分子机制。 本研究还将确定T1 D的潜在治疗试剂。

The type 1 diabetes (T1D) is an autoimmune disease that is caused by the permanent destruction of insulinproducing beta cells in pancreas by self-attacking immune cells. These self-attacking immune T cells are generally eliminated during development stage, and should be tolerized in the periphery if any leaking occurs. Therefore, a failure in the induction/maintenance of T-cell tolerance is crucial for T1D. However, the molecular mechanisms by which T-cell tolerance is induced/maintained remain largely unknown. Here we have found that loss of Sirt1 functions causes abnormally elevated immune responses and a break-down of peripheral tolerance of T cells. As a consequence, Sirt1-/- mice develop spontaneous autoimmunity. Those results indicate that Sirt1 is a negative regulator of T-cell activation and is required to maintain T-cell tolerance. It is therefore possible that mice without Sirt1 may develop T1D. Activation of Sirt1 by small molecules like resveratrol can potentially be used to treat T1D by inhibiting beta-cell-attacking autoimmune T cells. Indeed, results from a pilot study in our laboratory indicate that the activator of Sirt1, resveratrol, protected NOD mice from T1D. Therefore, this proposal aims to determine the molecular mechanisms underlying how Sirt1 functions an anergic factor of T-cells, and to investigate how dysregulated Sirt1 functions are involved in the development of T1D. We will also further determine the preventive/treating effects of resveratrol on T1D. Results from our proposed research are likely to uncover a novel molecular mechanism of T-cell tolerance. This study will also indentify potential therapeutic reagents for T1D.