m6A mRNA甲基化修饰调控TNFα合成的机理研究

TNFα是最重要的细胞因子之一，在损伤、修复、免疫应答、炎症反应以及造血中担任重要角色。TNFα的生物学合成受多种方式调控，包括转录起始调控、ARE元件介导的RNA翻译调控以及蛋白水平调控等，而其mRNA水平的表观遗传修饰调控目前仍不清楚。最新研究发现，m6A甲基化修饰是最丰富的内部mRNA修饰，参与调控mRNA代谢的多个过程。通过CRISPR-Cas9基因筛查系统和相关数据库我们发现TNFα的合成可能受m6A甲基化修饰调控。因此我们提出科学假设：m6A mRNA甲基化修饰调控TNFα的合成，从而影响免疫稳态维持。本项目拟解决如下科学问题：（1）m6A mRNA甲基化修饰调控TNFα合成的具体生物学机制；（2）m6A mRNA甲基化修饰调控TNFα合成的生理效应。对上述问题的探究有望发现调控TNFα合成的新方式和新机制，为治疗TNFα相关重大疾病提供新策略。

TNFα is one of the most important cytokines and plays important roles in injury, repair, immune response, inflammatory response and hematopoiesis. The biological synthesis of TNFα is regulated in a variety of ways, including transcriptional initiation regulation, RNA translation regulation mediated by ARE elements, and protein level regulation, while the epigenetic modification of its mRNA level is still unclear. Recent studies have found that m6A methylation is the most abundant internal mRNA modification, which is involved in multiple processes of regulating mRNA metabolism. Through the CRISPR-Cas9 gene-screening and related databases, we found that the synthesis of TNFα may be regulated by m6A methylation. Therefore, we propose a scientific hypothesis that m6A mRNA methylation regulates the synthesis of TNFα, and affects the maintenance of immune homeostasis. This project aims to solve the following scientific problems :(1) The specific biological mechanism of m6A mRNA methylation to regulate TNFα synthesis; (2) physiological effects of TNFα synthesis regulated by m6A mRNA methylation. To answer these questions will reveal new ways and mechanisms of regulating TNFα synthesis, and provide new strategies for the treatment of TNFα related major diseases.