Irisin在尿酸代谢及尿酸相关性肾损伤中的作用及机制研究

Accumulating evidence suggests that the prevalence of hyperuricemia increased year by year. As one important component of metabolic syndrome, it can result in a number of metabolic disorders. The traditional treatment of hyperuricemia includes restrain uric acid synthesis and promote excretion, however, reports have shown that both of them may lead some side effects. Therefore, it is particularly crucial to explore new therapeutic targets focus on lowering uric acid. Irisin is secreted form muscle, and the PGC1a-FNDC5-Irisin axis has been considered play an indispensable role in endocrine and energy metabolism. We have previously established that serum Irisin is closely related to uric acid, and after intervene with FNDC5, the level of uric acid changes as well, which indicate that Irisin may participate in the uric acid metabolism. As a result, this study will further systematically explore the the effect of Irisin on enzymes, transport protein, signaling pathway in uric acid metabolism pathway and the pathological injury of kidney. This study will also provide new insights into more effective interventions on hypeuricemia.

高尿酸血症的发病率逐年升高，作为代谢综合征的一个组成部分，它可以引起机体一系列代谢紊乱。目前用来治疗高尿酸血症的传统药物存在很多副作用，因此，深入探索尿酸代谢通路的调节因素为提供新的降尿酸治疗靶点显得尤为重要。Irisin是由肌肉细胞分泌的因子，PGC1a-FNDC5-Irisin轴在机体内分泌及能量代谢中发挥了不可忽视的作用。课题组前期在人群学研究中发现血清Irisin与尿酸浓度密切相关，此外，用重组FNDC5处理细胞后上清液的尿酸水平会发生变化，提示Irisin可能参与了尿酸的代谢过程。本研究拟在此基础上，通过动物、细胞培养双视角，全面系统地探讨Irisin对尿酸代谢通路上重要的酶、转运蛋白、信号通路的影响，以及对肾脏病理损伤的作用，从而明确Irisin在尿酸排泄通路中的作用及调控机制。有望为高尿酸血症的治疗提供新的理论依据。

高尿酸血症已经成为一个亟待解决的严峻的公共健康卫生问题。前期大量研究表明 Irisin 与许多疾病密切相关，其中包括肥胖、糖尿病、神经性厌食症、非酒精性脂肪肝、慢性肾脏疾病、代谢综合征等。我们前期已经开展了 irisin 与代谢性疾病及其并发症的系列研究，并发现血清 irisin 水平与血尿酸浓度存在显著相关性。本课题进一步收集临床资料验证前期发现的结果，发现irisin水平与尿酸相关的同时也与肝内脂肪含量相关。在动物模型及细胞水平观察注射FNDC5对小鼠表型及尿酸的影响及其可能的机制。此外，鉴于既往血尿酸水平在预测癌症中的作用在过去几十年一直是一个争论的问题，我们分析血清尿酸水平在胃黏膜癌变过程中的表达变化及其与癌变的相关性，并评价胃癌前病变及及胃癌筛查中血尿酸水平检测的作用，以为胃癌的防治及病情评估提供帮助。最后针对内分泌科常见肿瘤-甲状腺乳头状癌，探讨伴侣介导的自噬CMA对其发生发展的影响及其潜在机制。可能为PTC的治疗提供一个新靶点。本项目已发表SCI1篇，中文论著1篇，综述1篇，培养研究生1名。另有1篇SCI仍在投稿中。