Development of increasing functional HDL-C using antisense oligonucleotides as innovative therapy

使用反义寡核苷酸作为创新疗法开发增加功能性 HDL-C

• 批准号: 23591109
• 负责人: IWAMOTO Noriyuki
• 金额: $ 3.49万
• 依托单位: National Cardiovascular Center Research Institute
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2011
• 资助国家: 日本
• 起止时间: 2011 至 2013
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-23591109/
• 关键词: HDL; ABCA1; 核酸医薬

The objective of this basic research is to analyze whether or not innovative antisense oligonucleotides targeted specific molecular gene would be candidate of increasing serum HDL-cholesterollevel through the ABCA1/apoA-I pathway. We previously demonstrated that transcription factor AP-2 negatively regulates the ATP-binding cassette A1 (ABCA1) gene through its Ser-phosphorylation by protein kinase PKD which is a common modulator of the DNA binding activity of AP-2 through their phosphorylation for negative regulation of the ABCA in genes expression. The Antisense oligoniculeotide modified BNA is so innovative that have stronger effective compared to previous one.In this study, we demonstrated that the PKD specific targeted antisense could increase ABCA1 mRNA levels in liver in vitro and in vivo, which result in raising serum HDL-C level in vivo. To further develop this strategy, we need more experiments to figure out the value of efficacy and safety using oligonucleotides therapy

这项基础研究的目的是分析具有特定特定分子基因的创新反义寡核苷酸是否是通过ABCA1/APOA-I途径增加血清HDL-胆固醇级的候选。我们先前证明，转录因子AP-2通过蛋白激酶PKD通过其磷酸化来负调节ATP结合磁带A1（ABCA1）基因，这是AP-2的DNA结合活性通过其磷酸化的DNA结合活性的常见调节剂，用于基因表达中ABCA的负调节的磷酸化。反义寡酮修饰的BNA与先前的BNA相比具有更强的有效性。在这项研究中，我们证明了PKD特异性靶向反义可以在体外和体内提高肝脏中的ABCA1 mRNA水平，从而导致Vivo中提高血清HDL-C水平。为了进一步制定这种策略，我们需要更多的实验来弄清使用寡核苷酸疗法的功效和安全性的价值

项目成果

Involvement of protein kinase D in phosphorylation and increase of DNA binding of activator protein 2 alpha to downregulate ATP-binding cassette transporter A1

蛋白激酶 D 参与磷酸化并增加激活蛋白 2 α 的 DNA 结合，从而下调 ATP 结合盒转运蛋白 A1

• 发表时间: 2008
• 期刊: Arterioscler Thromb Vase Biol 28
• 作者: Hu W;Abe-Dohmae S;Tsujita M;Iwamoto N;Ogikubo 0;Otsuka T;Kumon Y;and Yokoyama S;Iwamoto N
• 通讯作者: Iwamoto N

Protein kinase D regulates the adiponectin gene expression through phosphorylation of AP-2: A common pathway to the ABCA1 gene regulation

• DOI: 10.1016/j.atherosclerosis.2011.01.043
• 发表时间: 2011-05-01
• 期刊: ATHEROSCLEROSIS
• 影响因子: 5.3
• 作者: Iwamoto, Noriyuki;Yokoyama, Shinji
• 通讯作者: Yokoyama, Shinji