结蛋白基因突变导致的结蛋白病是一种遗传性蛋白聚集性肌病，线粒体异常是结蛋白病最早发生的病理改变之一，然而导致线粒体异常的机制目前尚不完全清楚。电压依赖阴离子通道1（VDAC1）是线粒体渗透转化孔（PT孔）的重要组成亚基，当PT孔通透性增高时，大量细胞凋亡因子从线粒体基质中释放，导致细胞凋亡级联反应。细胞骨架蛋白对VDAC1有重要的调控作用，我们在结蛋白病的前期研究中发现：结蛋白和VDAC1可能存在直接的蛋白作用。本研究拟通过构建GST融合蛋白的方法，采用免疫共沉淀和重叠蛋白印迹等技术，进一步验证和确定结蛋白和VDAC1直接作用的结构域。同时采用多种表达质粒、RNA干扰和腺病毒包装质粒进行多种细胞和动物实验，检测结蛋白和VDAC1表达改变后，线粒体PT孔通透性改变规律，检测线粒体功能改变和线粒体介导的细胞凋亡级联反应。本研究将进一步揭示结蛋白病细胞内线粒体异常的机制，也为药物研发提供新靶点。

Desminopathy is a kind of hereditary protein aggregate myopathy caused by mutations in the desmin gene. Mitochondrial abnormality in the myocytes is one of early pathological characteristics of desminopathy, while its underlying pathogenesis is not completely clear and additional studies are required. Voltage-dependent anion channel 1 (VDAC1) is one of important subunits constructing mitochondrial permeability transition pore (PT pore). When the permeability of PT pore increased, multiple mitochondrial apoptogenic factors would be released into the cytosol, leading to the activation of mitochondrial induced-apoptosis cascade. There are several evidences demonstrating the interaction between cytoskeletal proteins and VDAC1. In our preliminary study about desminopathy, several mitochondrial abnormalities were related to VDAC1 dysfunctions, which indicated that desmin might directly interact with VDAC1. Therefore, we plan to construct GST recomninant VDAC1, and then determine the interaction domain between desmin and VDAC1 through GST pulldown, co-immunoprecipitation, and overlay immunoblot. Meanwhile, in order to explore the permeability of mitochondrial PT pore when the expression level of desmin and VDAC1 change, we establish several cell and animal models by expression vector transfections, RNA interference, adeno-associated virus mediated vectors injections. Making clearly the situation of mitochondrial dysfunction and mitochondrial induced-apoptosis cascade in desminopathy, it will shed light on the drug development of protein aggregate diseases.