锌剂干预肝豆状核变性的作用机制研究

Wilson’s disease (WD) is an autosomal recessive inherited disease associated with copper metabolism disorder. The pathogenic gene ATP7B encodes a copper transport protein, P-type ATPase, and deficiency of the protein will disturb the excretion of copper, accounting for progressive cirrhosis, neurological and psychiatric symptoms, renal dysfunction, and so on. WD is one of the few treatable genetic diseases, and the copper chelators and zinc are the primary therapeutic drugs. Copper chelators may worsen the neurological symptoms in some patients. As contrast, zinc is a relativly safe, cheap, and effective drug, which makes it an important role in the management of Wilson’s disease. However, the precise mechanism how zinc intervention works in WD remains unknown. On the basis of previous research, utilizing the established stable transfection WD cells and the introduced Atp7b-/- model mice, our project will investigate the protective role of zinc in different physiological and pathological process, explore its possible functional mechanism in WD treatment, and provide a theoretical and experimental foundation for clinical practise of zinc therapy .

肝豆状核变性 (Wilson’s disease, WD) 是一种与铜代谢障碍有关的常染色体隐性遗传病，其致病基因ATP7B编码一种铜转运P 型ATP 酶。ATP7B基因突变可导致患者排铜障碍，出现进行性加重的肝硬化、神经精神症状、肾功能损害等。肝豆状核变性是少数可治的神经遗传病之一，主要治疗药物是金属鳌合剂和锌剂。金属鳌合剂常导致肝豆状核变性患者的神经症状加重，因此，锌剂作为一种安全有效且价格低廉的药物，在治疗肝豆状核变性中起到举足轻重的作用，但其干预肝豆状核变性的具体作用机制迄今不清。本项目拟在前期研究基础上，利用已构建好的肝豆状核变性稳转细胞模型以及引进的Atp7b-/-小鼠模型，研究锌剂在不同生理病理过程中对疾病的保护作用，并探索锌剂干预肝豆状核变性的可能作用机制，为临床上锌剂治疗肝豆状核变性提供理论和实验依据。