了解结核病发病机制，是有效控制结核病的重要步骤。谷氨酰胺转胺6（TGM6）属于谷氨酰胺转胺酶家族，主要在神经系统疾病中发挥重要作用，其对免疫系统的调控作用未见报道。通过全基因组关联研究，我们首次报道TGM6是中国汉族人群结核病易感基因，但TGM6基因及rs6114027位点在结核病中的作用尚不清楚。我们前期研究发现，rs6114027位点能够调控TGM6的表达，TGM6能够抑制Akt活性影响结核菌感染过程中巨噬细胞的极化。在此基础上，本课题拟利用rs6114027位点敲入小鼠和TGM6基因敲除小鼠，从动物、细胞、分子三个层面，探讨rs6114027位点调控TGM6转录的机制；明确TGM6对结核菌感染巨噬细胞极化的调控作用；揭示TGM6通过聚胺化修饰抑制Akt活性调控巨噬细胞极化的分子机制。研究结果可为结核病发病机制研究提供新的理论基础，并为结核病遗传易感位点的生物学机制研究提供新的思路。

Understanding the pathogenesis of tuberculosis is very important for the control of tuberculosis. Transglutaminase-6 (TGM6), a member of the transglutaminase enzyme family, plays an important role in neurological diseases. The function of TGM6 in the immune system is unknown. By genome-wide association study, we first reported that TGM6 was a novel susceptibility gene for tuberculosis in Chinese Han population. However, the role of TGM6 gene and rs6114027 locus in the pathogenesis of tuberculosis remains unclear. Our previous study found that rs6114027 allele regulated the expression of TGM6, and TGM6 significantly promoted the polarization of macrophages during Mycobacterium tuberculosis (Mtb) infection by inhibiting the activity of Akt. In this project, we will further analyze the regulatory mechanisms of TGM6 expression, the role of TGM6 in polarization of macrophage during Mtb infection and the regulatory mechanisms of TGM6 in macrophage polarization from animal, cell and molecular levels by using rs6114027 knock-in mice and TGM6 knockout mice. The results of this study will provide a new insight into the pathogenesis of tuberculosis, and provide a new research model for us to study the biological function of genetic susceptible sites in tuberculosis.