IL-6/STAT3信号通路和脑内铁调素调节

项目名称： IL-6/STAT3信号通路和脑内铁调素调节

项目编号： No.31330035

项目类型： 重点项目

立项/批准年度： 2014

项目学科： 生物科学

项目作者： 钱忠明

作者单位： 复旦大学

项目金额： 270万元

中文摘要： 基于对外周hepcidin(铁调节激素)调控机制的认识，及我们对hepcidin在脑铁代谢中功能研究的结果，我们假设，“IL-6/JAK2/STAT3信号通路”可能是调控脑内铁调素表达的重要机制。为验证这假设，将系统分析LPS对大鼠脑皮层、海马和黑质及对这三脑区神经元、星形胶质细胞和小胶质细胞hepcidin表达的影响；系统研究LPS对这三脑区中IL-6、JAK2和STAT3磷酸化、以及对与小胶质细胞共同培养的神经元铁调素表达的影响；IL-6等及相关抗体或下调和上调STAT3磷酸化对神经元和多巴胺能细胞STAT3磷酸化或hepcidin表达的影响；也将研究跟STAT3直接结合的目标及其诱导铁调素表达的作用。本研究将帮助清楚阐明IL-6/STAT3信号通路在脑内铁调素表达调控中的作用，增进对脑铁代谢变化是否和神经退行性疾病发展相关这一问题的理解，并为研发防治铁相关神经退行性疾病新药提供坚实基础。

中文关键词： 铁调节激素;脑铁平衡;白细胞介素-6/信号转导和转录激活因子3；信号通路;调节和表达;炎症

英文摘要： Studies have shown that hepcidin plays an essential role in maintaining normal iron homeostasis in the periphery. We have previously demonstrated that lipopolysaccharides (LPS) can increase hepcidin expression in the cortex and substantia nigra (SN). However, the mechanism is unknown. Based on our understanding of hepcidin regulation in the periphery and the functions of hepcidin in brain iron metabolism, we speculated that the IL-6/STAT3 signal pathway is a key player in hepcidin expression in the brain. Experiments are designed to test this hypothesis. We will test the effect of LPS on hepcidin expression in different brain areas, and the role of microglia in the process. The exact roles of IL-6/STAT3 pathway in the regulation of hepcidin in different neuronal populations will also be examined directly by pharmacological and biochemical analyses. The results will greatly enhance our knowledge on the mechanisms involved in brain iron homeostasis and provide key information for the development of pharmacological interventions to disrupt the chain of pathological events occurring in neurodegenerative disorders.

英文关键词： Hepcidin;Brain iron homeostasis;IL-6/STAT3 signal pathway;Regulation and expression;Inflammation