Investigation of molecular mechanisms for common diseases caused by aging and oxidative stress and development of drug candidates aiming the molecular targets

本项目旨在研究脂肪细胞产生脂肪细胞因子和小胶质细胞清除β-淀粉样肽的分子机制，为开发靶向分子靶点的候选药物提供依据。在过去的三年中，我们获得了以下几项新发现和候选药物。(1) ox-LDL刺激可通过翻译调节机制增加抵抗素等部分脂肪细胞因子的产生。(2)我们发现了一种新的低聚β-淀粉样肽清除机制，该机制是由IL-4刺激选择性诱导的2型小胶质细胞。(3)利用转基因AD模型小鼠，验证了其体内诱导清除机制。我们还发现一些低分子量的化合物能够诱导清除机制。(4)成功制备了区分1型和2型小胶质细胞的特异性单克隆抗体（申请专利）。以上所描述的结果都超出了我们的预期，它们非常有希望为阿尔茨海默病的康复创造新的药物。

In this project we aim to investigate the molecular mechanisms for adipocytokine production from adipocytes and clearance of β-amyloid peptide in microglia, which apply to develop drug candidates aiming the molecular targets. During the passed three years, we have obtained several novel findings and drug candidates as follows. (1)Production of some adipocytokines including resistin increased by stimulation of ox-LDL via translation modulated mechanism. (2)We found a novel clearance mechanism of oligomeric β-amyloid peptides, which is induced selectively in type-2 microglia by IL-4 stimulation. (3)The clearance mechanism was proved to induce in vivo using transgenic AD model mice. We also found that some compounds of low molecular weight are able to induce the clearance mechanism. (4)We are succeeded in generating specific monoclonal antibodies to discriminate type-1 and type-2 microglia (Patent is applied.)All the results described above are more than we expected, and they are very promising to create new drugs for recovering from Alzheimer's disease, in particular.