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）是继发于糖尿病的严重并发症， 全球成人失明的头号原因。尽管最近的进步使用 然而，药物治疗，糖尿病视网膜病变的治愈尚未实现。进一步理解 导致疾病进展的分子事件将允许开发新的 治疗这种毁灭性疾病的方法。我们相信最近的证据表明 临床试验证明血脂异常与DR进展之间存在强相关性 以及发现肝脏X受体（LXRα/LXRβ）的药理学激活可以防止 在啮齿动物模型中的DR，为我们寻求DR的治愈提供了潜在的突破。 为了达到这一目的，我们建议分析SIRT 1-LXR在视网膜中的水平，并研究DR对视网膜的影响。 在SIRT 1-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。除了 通过测量SIRT 1和LXR的视网膜水平，我们还建议测量视网膜胆固醇， 在糖尿病人细胞以及糖尿病动物模型中的代谢物水平。这项建议 这为将人类供体视网膜表征为DR的不同阶段提供了独特的机会 通过使用新的成像拼接软件进行进展。这种创新的成像工具很容易 用于Busik实验室确定供体视网膜是否处于早期非增殖阶段 或者处于晚期增殖阶段。此外，为了确定这一途径的激活是否是一种 潜在的治疗DR在体内，我们建议分析SIRT 1-LXR激活的影响， 糖尿病动物模型。我们假设SIRT 1-LXR通路的激活将改善 对视网膜胆固醇代谢的有害作用，并减轻炎症状态 在糖尿病环境中很活跃密歇根州立大学拥有世界级的分子生物学和分子生物学专家。 代谢与疾病核心。因此，我们建议利用这些资源， 表征和分析对照组、DR早期以及 晚期增殖性DR阶段。此外，我们目前拥有激活 体内SIRT 1-LXR通路，使我们能够确定SIRT 1-LXR通路的激活是否 防止DR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.