FKBP51在糖皮质激素调节线粒体功能和线粒体蛋白转录因子表达中的作用

Mitochondrial function has received broad attention because of its impact on the pathophysiology of mental illness. Depression-related gene FKBP51 was found recently to enhance glucocorticoid receptor translocation into the mitochondria to regulate mitochondrial function.This project intends to study the role of FKBP51 in the molecular mechanism of glucocorticoid- induced anti-apoptotic Bcl-2 transferring into the mitochondria and protecting the cells, as well as the effects on the transcription factors of the mitochondrial proteins in the primary cortical neurons and the animal models. To reach the goals, co-immunoprecipitation would be used to determine whether the FKBP51 interacts with Bag-1 and Bcl-2 and translocates to the mitochondria after corticosterone treatment. Then, inhibition of FKBP51 expression by FKBP51 siRNA in the primary cortical neurons would be established to test whether FKBP51 is the molecular switch of the key molecule Bcl-2 translocation into the mitochondria to protect the mitochondrial functions. In addition, the impact of FKBP51 resulting from alteration of GR ratio in the nucleus and mitochondria on the expression of the transcriptional factors for mitochondria proteins would be determined. And then the application of these regulations in the rat chronic unpredicted mild stress animal model and the corticosterone-treated animal models would be studied. This project might further elaborate the mechanism of FKBP51 on nuclear receptor regulation of mitochondrial function and mitochondrial protein expression.

线粒体的功能因其和精神疾病的密切关系而得到广泛的关注。最近发现抑郁症相关基因FKBP51可增强糖皮质激素受体进入线粒体比率，并调节线粒体功能。本项目拟在大鼠大脑皮层原代神经元和大鼠动物长期束缚慢性应激模型中研究FKBP51如何调节糖皮质激素引发的线粒体Bcl-2水平变化、线粒体保护、及线粒体蛋白的转录因子的表达。拟先用免疫共沉淀确定经皮质酮处理后FKBP51是否和Bag-1及Bcl-2 相互作用形成复合物并转移到线粒体。并用FKBP51siRNA抑制其表达，以了解FKBP51是否是Bcl-2移位到线粒体并保护线粒体的功能的分子开关。并研究FKBP51调节糖皮质激素的受体在细胞核和线粒体中的比例是否会引起调控线粒体蛋白的转录因子特异表达，及这些功能调节在大鼠动物慢性不可预测温和应激抑郁模型和皮质酮处理动物模型中的作用。项目将发现抑郁症基因FKBP51影响糖皮质激素调节线粒体功能的新机制。