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

衰老和氧化应激引起的常见疾病的分子机制研究以及针对分子靶点的候选药物开发

• 批准号: 15390029
• 负责人: NAKAYAMA Hitoshi
• 金额: $ 9.73万
• 依托单位: Kumamoto University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2003
• 资助国家: 日本
• 起止时间: 2003 至 2005
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-15390029/
• 关键词: scavenger receptors; adipocytes; microglia; Alzheimer's disease; β-amyloid peptide; clearance; CD36; 肥満; Aβクリアランス; ACAT阻害剤; 脳虚血; CD3b

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.

在这个项目中，我们旨在研究MI Croglia中的脂肪细胞和透明肽的分子Medipolocytokine产生，这些肽适用于发展药物候选药物。通过IL-4刺激在2型小胶质细胞中选择性诱导。 ，特别是阿尔茨海默氏病。

项目成果

K.Furukawa, et al.: "Adiponectin down-regulates acyl-coenzyme A : cholesterol acyltransferase-1 in human monocyte-derived macrophages"Biochem.Biophys.Res.Commun.. (in press). (2004)

K.Furukawa 等人：“脂联素下调酰基辅酶 A：人单核细胞来源的巨噬细胞中的胆固醇酰基转移酶 1”Biochem.Biophys.Res.Commun.（出版中）。

Proteasomal degradation of Kir6.2 channel protein and its inhibition by Na^+ channel blocker aprindine.

Kir6.2 通道蛋白的蛋白酶体降解及其 Na+ 通道阻断剂阿普林定的抑制。

• 发表时间: 2005
• 期刊: Biochem.Biophys.Res.Commun. 331
• 作者: Tanaka;H. et al.
• 通讯作者: H. et al.

Characterization of benzodiazepine binding site on human α-1-acid glycoprotein.

人 α-1-酸性糖蛋白上苯二氮卓结合位点的表征。

• 发表时间: 2005
• 期刊: Biochim.Biophys.Acta 1725
• 作者: Chuang;V.T.G.et al.
• 通讯作者: V.T.G.et al.

Use of photoaffinity labeling and site-directed mutagenesis for identification of key residue responsible for extraordinarily high affinity binding of UCN-01 in human alpha 1-acid glycoprotein

使用光亲和标记和定点诱变来鉴定负责人 α1-酸性糖蛋白中 UCN-01 极高亲和力结合的关键残基

• 发表时间: 2005
• 期刊: J.Biol.Chem. 280
• 作者: M.Katsuki;et al.
• 通讯作者: et al.

Proteasomal degradation of Kir6.2 channel protein and its inhibition by Na+ channel blacker aprindine.

Kir6.2 通道蛋白的蛋白酶体降解及其 Na 通道黑阿普林定的抑制。

• 发表时间: 2005
• 期刊: Biochem.Biophys.Res.Commun. 331
• 作者: H.Tanaka;et al.
• 通讯作者: et al.