Calhm2调控的神经炎症在阿尔兹海默病中的功能和机制研究

钙稳态失衡是神经炎症产生和AD发生的重要原因，但是该过程的关键分子和调控机制还尚不清楚。已有报道提示CALHM家族蛋白作为钙稳态维持的重要分子参与AD的发生，我们前期的工作发现Calhm2敲除可以有效减轻AD模型小鼠的空间认知损伤，显著降低脑内Aβ沉积和胶质细胞激活。体外的实验进一步证实Calhm2敲除可以有效抑制NLRP3炎症小体的活化，增加小胶质细胞的吞噬能力。同时，我们发现Calhm2突变V136G与AD的发生密切相关。在此基础上，本课题拟利用神经生物学、分子生物学、药物化学等技术手段，结合原代神经细胞，基因敲除小鼠，疾病模型小鼠、临床病人样本，深入研究Calhm2在小胶质细胞激活过程中的作用和分子机制，进而阐明Calhm2调控的神经炎症在AD中作用和分子机制，同时结合临床AD样本，分析Calhm2突变与疾病发生的相关性，最终为AD的临床诊治提供理论依据和可能的治疗靶点。

Calcium dyshomeostasis is one of the main reasons for the occurrence of neuroinflammation and Alzheimer’s disease (AD), however, the key molecular and regulatory mechanism are still not clear. It has been reported that calcium homeostasis modulator family member proteins (CALHM) take important roles in the development of AD. Our previous data showed that knockout of Calhm2 significantly ameliorates the learning and memory of AD mice, and decreases the levels of Aβ deposition and neuroinflammation. In vitro studies further showed that knockout of Calhm2 inhibits the activation of NLRP3 inflammasome and amplifies the activity of microglial phagocytosis. In addition, we found that the mutation V136G of Calhm2 is closely associated with the occurrence of AD. Base on these results, we will use the technologies of neurobiology, molecular biology, pharmaceutical chemistry, together with primary cells, knockout mice, AD model mice, clinical AD patients samples, aiming to study the role and underlying molecular mechanism of Calhm2 in the microglial activation, neuroinflammation and AD development. In addition, we will analyze the relationship between the mutation of Calhm2 and occurrence of AD, Together, our work will pave a novel avenue for the prevention and treatment for AD.