GDF15调控线粒体功能在帕金森病发生发展中的作用机制研究

Parkinson's Disease (PD) is the second largest neurological degeneration disease in the world. Currently there is no diagnostic biomarkers, therefore it is still a clinical diagnosis. Besides, we are also confronting other problems from PD, such as there is no effective treatment to stop it from progression. To further understand PD’s pathogenesis and best regimen for it, researchers are devoted to the study of modification therapy. Several studies have shown that PD is closely related to mitochondrial dysfunction, and GDF15 plays a significant role in the regulation of mitochondrial function. Our previous study indicated that the serum concentration of GDF15 are remarkably elevated in patients with PD, and it also correlates with disease severity; exogenous GDF 15 can enhance the metabolism rate and oxidative respiration of HT22 cell lines. Moreover, researches have confirmed that P53 and PPARγ, which can induce the expression of GDF15, are strongly linked with the mitochondrial function in dopaminergic neurons, whereas GDF15 can inhibit p53 expression by Akt/mTOR pathway and upregulate the level of PPARγ. We intend to measure the level of GDF15 in peripheral blood and cerebrospinal fluid, to identify the relationship between GDF15 and Parkinson's Disease. Furthermore, we plan to investigate the role of GDF15 in mitochondrial function regulation in Parkinson’s Disease, by its interaction with p53, PPARγ on a molecular level in cell cultures and mouse models (PD model). To achieve this goal, we will use techniques as below: knockout, overexpression, or exogenous addition of GDF15 and so on. Through the analysis of the large sample clinical cases, it would be helpful to explore whether GDF15 can act as a biomarker for monitoring progression and provide new breakthrough for modification therapy of PD.

帕金森病（Parkinson’s disease, PD）是世界第二大神经系统变性疾病，其诊断标准以临床症状为核心依据，尚无理想的生物学标志物；PD的治疗仍是对症治疗，无法阻止病情进展，疾病修饰治疗是治疗的关键。线粒体功能异常与PD发生密切相关，有研究认为GDF15是调控线粒体功能的重要因子。我们前期研究发现: PD患者外周血GDF15含量显著增加，且与疾病的严重程度相关；而外源性GDF15能增强细胞能量代谢速率和氧化呼吸能力。我们拟在PD患者-健康对照的外周血和脑脊液、PD动物模型及细胞模型三个层面上，通过GDF15敲除/过表达、外源添加GDF15等分子生物学方法，观察GDF15能否通过与p53、PPARγ相互作用调控PD线粒体功能及其分子机制。通过对大样本病例分层分析，明确GDF15是否能成为监测疾病发生发展的生物学标志物，探讨以线粒体为靶向的PD治疗策略。

帕金森病（Parkinson’s disease, PD）是世界第二大神经系统变性疾病，其诊断标准 以临床症状为核心依据，尚无理想的生物学标志物；PD的治疗仍是对症治疗，无法阻止病情进 展，疾病修饰治疗是治疗的关键。线粒体功能异常与PD发生密切相关，有研究认为GDF15是调 控线粒体功能的重要因子。我们前期研究发现: PD患者外周血GDF15含量显著增加，且与疾病 的严重程度相关；而外源性GDF15能增强细胞能量代谢速率和氧化呼吸能力。我们拟在PD患者 健康对照的外周血和脑脊液、PD动物模型及细胞模型三个层面上，通过GDF15敲除/过表达、外 源添加GDF15等分子生物学方法，观察GDF15能否通过与p53、PPARγ相互作用调控PD线粒体功 能及其分子机制。通过对大样本病例分层分析，明确GDF15是否能成为监测疾病发生发展的生 物学标志物，探讨以线粒体为靶向的PD治疗策略。