A Unique Receptor Agonist Approach for Type 1 Diabetes Prevention

项目摘要 1型糖尿病(T1D)是由自身免疫介导的胰岛素产生β-受体破坏所致。 朗格汉斯人胰岛内的细胞。炎性事件、白细胞渗入和破坏 胰岛β细胞是疾病发生的关键因素。我们假设抑制促炎反应 刺激会减少导致T1D的致病机制。为了实现这一目标，我们建议 研究不同的糖皮质激素受体(GR)激动剂的使用情况，这些药物尚未上市 抑制胰岛的炎症反应。我们发表的使用小鼠、大鼠和人类的研究 胰岛已经显示出有希望的结果，促使人们追求体内临床前概念验证研究来 解决导致自身免疫的基本生物学过程及其抑制，方法是 GR.我们提出了两个具体目标来研究这种创新疗法的疗效和副作用。 接近。在特定的目标1中，我们将使用多次小剂量注射链脲佐菌素模型来研究 新型糖皮质激素受体激动剂抑制大鼠急性炎症反应的体内实验研究 最终导致高血糖的胰岛。行为和代谢的副作用将是 与主要的免疫和生理终点一起监测。在具体目标2中，我们将 研究我们的GR激动剂方法是否能预防非肥胖糖尿病(NOD)小鼠的糖尿病 慢性炎症模型，显示与以下相关的经典自身免疫机制的自发发病 人类T1D。了解创新型糖皮质激素受体的原理和机制 激动剂方法对抑制、治疗和治愈自身免疫性疾病具有重要意义。

Project Summary Type 1 diabetes mellitus (T1D) results from autoimmune-mediated destruction of the insulin-producing beta- cells within the pancreatic islets of Langerhans. Inflammatory events, infiltrating leukocytes, and destruction of islet beta-cells are key contributors to disease onset. We hypothesize that suppressing pro-inflammatory stimuli will reduce the disease causing mechanisms leading to T1D. Towards this goal, we propose to investigate the use of distinct glucocorticoid receptor (GR) agonists, which are not commercially available, to suppress inflammatory responses in pancreatic islets. Our published studies using mouse, rat, and human islets have indicated promising results, prompting a pursuit of in vivo pre-clinical proof of concept studies to address the basic biological processes contributing to autoimmunity and their suppression by engaging the GR. Two specific aims are proposed to investigate the efficacy and side effects of this innovative therapeutic approach. In Specific Aim 1, we will use the multiple low dose injection of streptozotocin model to investigate the in vivo effectiveness of novel glucocorticoid receptor agonists to suppress the acute inflammatory events in pancreatic islets that ultimately produce hyperglycemia. Behavioral and metabolic side effects will be monitored along with the primary immunological and physiological endpoints. In Specific Aim 2, we will investigate whether our GR agonist approach prevents diabetes in the non-obese diabetic (NOD) mouse, a model of chronic inflammation that displays spontaneous onset of classic autoimmune mechanisms relevant to human T1D. Understanding the principles and mechanisms underlying innovative glucocorticoid receptor agonist approaches have important implications for suppressing, treating, and curing autoimmune diseases.