钴是阿尔茨海默病（AD）重要环境诱因之一，但致病机制不明。神经细胞铁死亡及RNA的m6A甲基化修饰失调均与AD相关，二者是否共同参与环境毒物致神经退行性损害尚不清楚，且未见报道。我们首次发现氯化钴可致小鼠脑内铁代谢紊乱及神经细胞铁死亡，提示铁死亡参与氯化钴致AD进程。进一步研究发现血红素加氧酶HO-1可能调控氯化钴致细胞铁死亡，且m6A去甲基化酶ALKBH5可能调控HO-1转录后表达。因此提出假设：ALKBH5介导HO-1 mRNA的m6A修饰调控氯化钴致神经细胞铁死亡。本项目拟采用基因工程与RNA表观遗传毒理学技术，通过体外细胞和整体小鼠实验，进一步明确氯化钴致神经细胞铁死亡作用特征，阐明HO-1在氯化钴致神经细胞铁死亡中的调控作用及机制，揭示ALKBH5对HO-1转录后表达调控机制及其在氯化钴致神经细胞铁死亡中的作用，为环境毒物效应与机制研究拓宽新思路，为AD精准防控提供新的分子靶点。

Cobalt is one of the potential environmental risk factors for Alzheimer's disease (AD). However, the pathogenic mechanism of cobalt is still unclear. New studies showed that ferroptosis and N6-methyladenosine (m6A) modification of RNA alterations are both important pathways for AD. However, it is not clear if the two processes are jointly involved in the neurodegenerative damage induced by environmental toxins. In previous studies, we found that cobalt chloride could cause iron metabolism disorder in mice brain and induce neuronal ferroptosis, suggesting that ferroptosis could be involved in the process of cobalt induced neurodegenerative diseases such as AD. Further studies showed that heme oxygenase (HO-1) regulated neuronal ferroptosis caused by cobalt chloride. HO-1 is regulated by ALKBH5 (alkylation repair homolog protein 5), which is a critical methyltransferase for the m6A RNA methylation. Therefore, we hypothesized that ALKBH5 could change the level of m6A modification of HO-1 and regulate neuronal ferroptosis induced by cobalt chloride. We plan to apply experimental techniques of gene overexpression/inhibition and epigenetics, through both in vivo animal model and in vitro human brain glioma cells to clarify the characteristics of cobalt chloride induced neuronal ferroptosis, elucidate the molecular mechanism of m6A methylation modification of HO-1 in cobalt chloride induced neuronal ferroptosis, and reveal possible regulatory role of ALKBH5 for the expression of HO-1 during the process. This project will provide innovative insight for the research of pathogenic mechanism of environmental risk factors, and provide potential targets for the prevention and treatment of AD.