PMP22介导的足细胞骨架重构在FSGS发病中的作用研究

FSGS是一种典型的足细胞病，针对参与足细胞损伤过程分子的靶向治疗为FSGS的诊治开辟了一个新领域。PMP22广泛表达于包括肾脏在内的全身组织，其表达的异常增多可导致腓骨肌萎缩症（CMT），CMT患者可合并有FSGS，提示两种疾病可能存在共同的分子机制。我们预实验发现：在原发性FSGS的肾小球中PMP22的表达明显增加；在足细胞中过表达PMP22，ITGA3的表达出现明显下降，足细胞F-actin的丝状结构消失，但作用机制未明。由此，我们首次提出FSGS发病中的新机制：PMP22可以负调控ITGA3，PMP22表达的增加使ITGA3的表达下降，引起足细胞骨架失稳。本课题拟进一步证实PMP22的表达异常与FSGS的关系；深入揭示PMP22对ITGA3基因表达转录的调控机制；在细胞和动物模型中，证实PMP22对足细胞功能损伤作用，为FSGS的治疗提供新的靶点。

FSGS is believed to be a classic kind of podocyte disease, targeted therapies for molecules involved in podocyte injury show good effects. PMP22 is widely expressed in many tissues including kidney. Overexpression of PMP22 could lead to CMT, and some CMT patients also have FSGS, which suggests there exists common mechanisms in CMT and FSGS. In previous study, we found that expression of PMP22 is up-regulated in podocytes in primary FSGS. The expression of integrin alpha 3 (ITGA3) is decreased and the organization of the F-actin is disappeared in PMP22 overexpression podocyte. Hence, we presume the new mechanism of FSGS: PMP22 can regulate ITGA3 negatively, and the increasing expression of PMP22 could down-regualte ITGA3 expression, which contributes to disorganization of cytoskeleton in podocyte. In this study, we will further examine the association between overexpression of PMP22 and FSGS, and explore the mechanism for ITGA3 regulation by PMP22 deeply. At last, the effect of PMP22 on podocyte injury will be confirmed in podocyte or FSGS animal model, which will provide a new target in FSGS therapies.