A novel target for type 1 diabetes

1型糖尿病(T1D)是一种自身免疫性疾病，由自身攻击的免疫细胞永久破坏胰腺中产生胰岛素的β细胞引起。这些自我攻击的免疫T细胞通常在发育阶段被消除，如果发生任何泄漏，应该在外围容忍。因此，T细胞耐受性的诱导/维持失败对T1D至关重要。然而，分子 诱导/维持T细胞耐受的机制在很大程度上仍不清楚。在这里，我们发现Sirt1功能的丧失会导致免疫反应异常升高和T细胞外周耐受性的崩溃。结果，Sirt1-/-小鼠产生了自发的自身免疫。这些结果表明，Sirt1是T细胞激活的负性调节因子，是维持T细胞耐受所必需的。它是 因此，没有Sirt1的小鼠可能会患上T1D。白藜芦醇等小分子激活Sirt1可通过抑制β细胞攻击自身免疫T细胞来潜在地用于治疗T1D。事实上，我们实验室的一项初步研究结果表明，Sirt1的激活剂白藜芦醇可以保护NOD小鼠免受T1D的影响。 因此，本研究旨在确定Sirt1作为T细胞无能因子发挥作用的分子机制，并探讨Sirt1功能异常如何参与T1D的发生发展。我们还将进一步确定白藜芦醇对T1D的预防/治疗作用。 我们提出的研究结果可能揭示T细胞耐受的一种新的分子机制。 这项研究还将确定治疗T1D的潜在治疗试剂。

The type 1 diabetes (T1D) is an autoimmune disease that is caused by the permanent destruction of insulin producing 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.