A novel target for type 1 diabetes

1 型糖尿病的新靶点

• 批准号: 8012354
• 负责人: Deyu Fang
• 金额: $ 9.77万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-03-01 至 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8012354
• 关键词: Autoimmune Diseases; Autoimmune Process; Autoimmunity; Beta Cell; Cells; Development; Failure; Immune; Immune response; Inbred NOD Mice; Insulin-Dependent Diabetes Mellitus; Laboratories; Maintenance; Molecular; Mus; Pancreas; Pilot Projects; Preventive; Reagent; Research; Resveratrol; Staging; T-Cell Activation; T-Lymphocyte; TCF Transcription Factor; Therapeutic; novel; peripheral tolerance; small molecule; Autoimmune Diseases; Autoimmune Process; Autoimmunity; Beta Cell; Cells; Development; Failure; Immune; Immune response; Inbred NOD Mice; Insulin-Dependent Diabetes Mellitus; Laboratories; Maintenance; Molecular; Mus; Pancreas; Pilot Projects; Preventive; Reagent; Research; Resveratrol; Staging; T-Cell Activation; T-Lymphocyte; TCF Transcription Factor; Therapeutic; novel; peripheral tolerance; small molecule

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.

1型糖尿病（T1D）是一种自身免疫性疾病，是由永久破坏胰岛素产生引起的 胰腺中的β细胞通过自动攻击免疫细胞。这些自我攻击的免疫T细胞是 通常在开发阶段消除，如果发生任何泄漏，应在外围耐受。 因此，T细胞耐受性的诱导/维持失败对于T1D至关重要。但是，分子 诱导/维持T细胞耐受性的机制仍然在很大程度上未知。我们在这里找到了 SIRT1功能的损失导致免疫反应异常升高，并且是周围的。 T细胞的耐受性。结果，SIRT1 - / - 小鼠会自发自动免疫。这些结果 表明SIRT1是T细胞激活的负调节剂，需要维持T细胞耐受性。这是 因此，没有SIRT1的小鼠可能会​​发展为T1D。小分子激活SIRT1 白藜芦醇可以通过抑制β细胞的自身免疫性T细胞来可能用于治疗T1D。的确， 我们实验室的一项试点研究的结果表明，SIRT1的激活剂，白藜芦醇，保护小鼠 来自T1D。 因此，该建议旨在确定SIRT1如何发挥作用的分子机制 T细胞的抗激因素，并研究SIRT1功能如何与 T1D。我们还将进一步确定白藜芦醇对T1D的预防/治疗作用。 我们提出的研究的结果可能会发现T细胞耐受性的新型分子机制。 这项研究还将缩减T1D的潜在治疗试剂。