TREM2基因的表达调控研究及靶向药物筛选

Recently, a novel variant in the gene encoding the triggering receptor expressed on myeloid cells 2 (TREM2) has been identified that has refocused the spotlight back onto inflammation as a major contributing factor in AD. Variants in TREM2 triple one’s risk of developing late-onset AD. TREM2 is expressed on microglial cells, and functions to stimulate phagocytosis of Aβ and apoptotic neurons on one hand and to suppress cytokine production and inflammation on the other hand. Therefore, increasing the expression level of TREM2 has great potential to cure and prevent AD. Although the important function of TREM2 has been well acknowledged, the TREM2-related signaling pathway remains elusive. Regulation of TREM2 transcription especially in microglia also remains largely unknown. In this proposal, we intend to investigate the TREM2 expression regulation mechanism in microglial cells. And we hope to clarify how TREM2 expression is modulated during the disease progress. We would also screen for small molecular compounds from a homemade natural compound library that could induce TREM2 expression. Finally, we would investigate the efficacy of using those compounds for AD prevention and therapy.

TREM2是最近发现的阿尔茨海默病（AD）的风险基因，其编码区突变会增加近三倍罹患AD的风险。大脑中Aβ的大量沉积、神经细胞的凋亡以及炎症反应的级联放大是AD的病理特征。TREM2具有潜在的吞噬Aβ、清除凋亡的神经细胞、限制炎性因子的表达与释放等功能，因而大脑中提高TREM2的表达很可能有助于AD的预防和治疗。TREM2在神经系统中主要表达于小胶质细胞，然目前关于TREM2在小胶质细胞中的表达调控机制、详细作用机理和上下游信号通路均尚未可知。因而，我们拟深入探讨TREM2在小胶质细胞中的表达调控机制，理清TREM2表达水平在AD病理过程中的变化谱式。同时，我们将利用课题组已有的天然小分子化合物库，筛选出能够诱导TREM2高表达的化合物并阐明其作用机理及其对AD病程的改善情况。

TREM2是新近发现的阿尔茨海默病（AD）的风险基因，其编码区R47H突变增加近三倍AD的发生风险。TREM2在神经系统中主要表达于小胶质细胞，TREM2在小胶质细胞中的表达调控机制、生物学功能以及相关的信号通路目前尚未完全解析。本项目探讨了TREM2在小胶质细胞中的表达调控机制，以及TREM2表达变化对小胶质细胞功能的影响。同时，本项目揭示了TREM2调控小胶质细胞功能的信号通路，并筛选获得能够调控TREM2表达水平的小分子化合物。此外，本项目还探讨了TREM2的胞外可溶性片段（Soluble TREM2，sTREM2）在小胶质细胞中的功能，进一步丰富了原计划的内容，更加全面地解析了TREM2的生理功能。