Molecular mechanism of alteration of intracellular traffic of LDL receptor by PCSK9

2020 Fiscal Year Final Research Report

• Project/Area Number: 19K22632
• Research Category: Grant-in-Aid for Challenging Research (Exploratory)
• Allocation Type: Multi-year Fund
• Review Section: Medium-sized Section 54:Internal medicine of the bio-information integration and related fields
• Research Institution: Tohoku University
• Principal Investigator: Horiuchi Hisanori 東北大学, 加齢医学研究所, 教授 (90291426)
• Project Period (FY): 2019-06-28 – 2021-03-31
• Keywords: PCSK9 / 低比重リポ蛋白質受容体 / 家族性高コレステロール血症

Outline of Final Research Achievements

When PCSK9 binds LDL receptor (LDLR) extracellularly, LDLR receptor does not become recycle back to plasma membrane from endosome, but transported to lysosome, resulting in degradation in lysosome, decrease of cellular LDLR, and decrease incporporation of LDL into cethe cell. So far, the intracellular function of PCSK9 remains to be elucidated. In the study, we have tried to develop a experession cloning ssytem to find a nanobody, immnoglobulin of Camel consisting of one protein. Then, we tried to identify factors involved in the PCSK9 pathway by alteration of the expression levels of genes of already-known proteins, which have been demonstrated to bind to intracellular domain of LDLR. We are under improvement of these projects.

Free Research Field

生化学、内科学

Academic Significance and Societal Importance of the Research Achievements

家族性高コレステロール血症の10％はPCSK9の遺伝子変異であり、またPCSK9阻害薬がコレステロール降下薬として診療現場で使われている。本研究は、PCSK9の細胞内での作用メカニズムを明らかにすることで薬剤の理解を深め、さらにこの経路での新規重要因子の発見は、新たな薬剤ターゲットとなろう。そのため、完成に向け、本能ロジェクトを継続、発展させている。