A novel target for type 1 diabetes

1型糖尿病（T1 D）是一种自身免疫性疾病，其由胰腺中产生胰岛素的β细胞被自我攻击的免疫细胞永久性破坏而引起。这些自我攻击的免疫T细胞通常在发育阶段被消除，并且如果发生任何泄漏，则应该在外周中耐受。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T细胞外周耐受性的破坏。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细胞活化的负调节因子，并且是维持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。通过白藜芦醇等小分子激活Sirt 1可以通过抑制β细胞攻击自身免疫T细胞来治疗T1 D。事实上，我们实验室的一项初步研究结果表明，Sirt 1的激活剂白藜芦醇可以保护NOD小鼠免受T1 D的影响。 因此，本研究旨在确定Sirt 1作为T细胞无反应性因子的分子机制，并研究Sirt 1功能失调如何参与T1 D的发展。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 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.