The role of the SIRT1-LXR signaling axis in diabetes-induced cholesterol metabolism dysregulation

项目摘要 糖尿病视网膜病变(DR)是糖尿病继发的严重并发症，是 全球成人致盲的头号原因。尽管最近取得了进展，但使用 药物治疗是治疗糖尿病视网膜病变的一种方法，目前还没有实现。进一步认识 导致疾病进展的分子事件将为开发新的 这一毁灭性疾病的治疗方案。我们认为最近有证据表明， 临床试验显示血脂异常与糖尿病视网膜病变进展密切相关 以及发现肝X受体(lxrα/lxrβ)的药理激活可防止 在啮齿动物模型中，DR为我们寻求Dr.的治愈提供了一个潜在的突破，以实现这一点 我们建议分析视网膜中SIRT1-LXR的水平，并研究DR对视网膜的影响 在SIRT1-LXR信号轴上。这个信号轴促进胆固醇的激活 代谢途径，以及防止促炎基因的上调。此外 测量视网膜中SIRT1和LXR的水平，我们还建议测量视网膜胆固醇 糖尿病人细胞和糖尿病动物模型中的代谢物水平。这项建议 为将人类供体视网膜描述为DR的不同阶段提供了独特的机会 通过使用一种新的成像拼接软件进行进展。这一创新的成像工具很容易 Busik实验室用于确定供体视网膜是否处于早期、非增殖期 或者处于晚期、增殖期。此外，为了确定该通路的激活是否是一种 体内治疗糖尿病视网膜病变的可能性，我们建议分析SIRT1-LXR激活对糖尿病视网膜病变的影响。 糖尿病动物模型。我们假设SIRT1-LXR通路的激活将会改善 对视网膜胆固醇代谢和减轻炎症状态的有害影响 在糖尿病环境中表现活跃。密歇根州立大学拥有世界级的分子 新陈代谢与疾病核心。因此，我们建议利用这一资源，进一步 描述和分析对照组、早期糖尿病视网膜病变患者和 增殖期晚期DR。此外，我们目前有必要的工具来激活 体内的SIRT1-LXR通路，使我们能够确定SIRT1-LXR通路的激活 防止DR的形成。

Project Summary Diabetic retinopathy (DR) is a critical complication secondary to diabetes and is the number one cause of blindness in adults worldwide. Despite recent advances using pharmacotherapy, a cure for diabetic retinopathy has yet to be realized. Further understanding of the molecular events that cause disease progression will allow for the development of novel therapeutic solutions for this devastating disease. We believe that recent evidence from large clinical trials demonstrating a strong association between lipid abnormalities and DR progression as well as the discovery that pharmacological activation of liver X receptor (LXRα/LXRβ) prevents DR in rodent models, offers a potential breakthrough in our search for cure of DR. To achieve this goal, we propose to analyze retinal levels of SIRT1-LXR as well as investigate the impact DR has on the SIRT1-LXR signaling axis. This signaling axis promotes activation of cholesterol metabolism pathways as well as prevents upregulation of pro-inflammatory genes. Besides measuring retinal levels of SIRT1 and LXR, we also propose to measure retinal cholesterol metabolite leves in diabetic human cells as well as in an animal model of diabetes. This proposal allows for the unique opportunity to characterize human donor retinas into distinct stages of DR progression by using a novel imaging stitching software. This innovative imaging tool is readily used in the Busik Laboratory to determine if donor retinas are in the early, non-proliferative stage or are in the late, proliferative stage. Additionally, to ascertain if activation of this pathway is a potential therapy for DR in vivo, we propose to analyze the effect of SIRT1-LXR activation in a diabetic animal model. We hypothesize that activation of the SIRT1-LXR pathway will improve the deleterious effects seen on retinal cholesterol metabolism and alleviate the inflammatory state active in the diabetic milieu. Michigan State University is home to a world class Molecular Metabolism and Disease Core. Thus, we propose to take advantage of this resources to further characterize and analyze retinal cholesterol levels between control, early stages of DR as well as late proliferate DR stages. Additionally, we currently have the tools necessary to activate the SIRT1-LXR pathway in vivo, allowing us to determine if activation of the SIRT1-LXR pathway prevents DR formation.