Wnt信号通路在砷致肺组织病变中的调控作用

Objective: The arsenic poisoning hazards wide range of people, and affected offspring and to generate long-term effects, but there remains unclear arsenic poisoning and carcinogenic mechanisms of arsenic poisoning prevention is also an urgent need to solve the problem. Previous studies suggest that ROS-mediated mechanism of arsenious acid in normal and malignant cells process to protect cells from free radical-mediated damage. Wnt signaling pathway is involved in the pathological changes of the multi-system, Study has confirmed that the ROS-mediated Wnt / β-catenin signaling pathway is a potential pathogenic mechanisms of arsenic. The study intends to by arsenic poisoning animal models and human embryonic lung fibroblast model, the application of molecular probes, RNA interference ，reverse transcriptase RT-PCR, Western blot technology from the whole - cell - molecular level environment from in vitro - in vivo environment, clarify ROS-mediated Wnt signaling pathway blockade before and after the intervention role to play in the pathogenesis of inorganic arsenic. Further reveal arsenide poisoning and carcinogenic mechanism and its control, to provide a scientific basis as well as new ideas.

砷中毒危害的人群众多，并且影响深远，而砷致病机制仍不明确，因此防治砷中毒是目前急需解决的问题。有研究提示亚砷酸钠毒作用过程存在ROS的影响，而Wnt信号通路涉及到多系统的病理变化，该信号转导通路也是砷致病的潜在机制。本研究拟建立慢性砷中毒大鼠动物模型砷染毒的动物模型，应用分子探针、RNA干扰、逆转录RT-PCR、免疫印迹等技术，阐明砷对肺组织毒性作用过程中Wnt信号通路发挥的信号转导的分子机制；及靶向siRNA阻断Wnt/β-catenin信号通路后，对砷的肺组织毒性作用调控作用。研究Wnt信号通路在砷致HELF细胞毒性中的生物学效应；及靶向siRNA阻断Wnt信号通路对砷致HELF细胞毒性的干预机制。从整体-细胞-分子层次，从体外环境-体内环境，阐明ROS介导的Wnt信号通路阻断前后在无机砷致病机制中发挥的干预调控作用，为进一步揭示砷致病机制及其防治，提供科学依据以及新的思路。

砷中毒危害广泛深远，而砷致病机制仍不明确，因此揭示砷毒作用机制，防治砷中毒十分必要。本研究建立慢性砷中毒SD大鼠动物模型，以及砷致HELF 细胞损伤模型，应用分子探针、RNA 干扰、逆转录RT-PCR、免疫印迹等技术，阐明砷在体内及体外对肺的毒性作用过程中，ROS介导的Wnt 信号通路发挥的信号转导的分子机制；及靶向siRNA 阻断Wnt/β-catenin 信号通路后，对砷致肺毒性作用的调控作用。研究发现，砷会抑制动物生长，长期接触砷，会导致砷在体内蓄积并产生肺损伤病变，导致体内产生氧化应激损伤。砷可抑制HELF细胞正常生长，使HELF细胞的氧化应激损伤作用增强，抑制细胞增殖，诱导细胞凋亡。无论体内动物实验还是体外细胞研究，均证实砷可以对Wnt/-catenin信号通路产生抑制作用，而该抑制效应可能与肺组织损伤有关。靶向siRNA 阻断Wnt信号通路后，砷致肺毒性作用增强，进一步加剧了Wnt/-catenin信号通路的异常表现，推测这也可能是砷致肺毒性增加的原因。本次研究为进一步揭示砷致病机制及其防治，提供科学依据以及新的思路。