Analysis of the pathogenesis of cerebral cavernous malformations using patient-derived xenografts

2022 Fiscal Year Final Research Report

• Project/Area Number: 21K20985
• Research Category: Grant-in-Aid for Research Activity Start-up
• Allocation Type: Multi-year Fund
• Review Section: 0906:Surgery related to the biological and sensory functions and related fields
• Research Institution: The University of Tokyo
• Principal Investigator: Hongo Hiroki 東京大学, 医学部附属病院, 助教 (80908682)
• Project Period (FY): 2021-08-30 – 2023-03-31
• Keywords: 脳海綿状血管奇形 / 遺伝子変異 / 動物モデル

Outline of Final Research Achievements

By sequencing several vascular malformations, including orbital cavernous venous malformations (OCVMs), we identified that a somatic missense mutation, c.121G > T (p.Gly41Cys) in GJA4 is frequently present in OCVMs. Functional analysis revealed the mutation to be a gain-of-function mutation that induces a hyperactive hemichannel, which subsequently induces the loss of normal function of endothelial cells. In addition, we generated genetically engineered mice in which the Gja4 mutation is knocked-in.

Free Research Field

脳血管疾患

Academic Significance and Societal Importance of the Research Achievements

海綿状血管奇形において新規の関連遺伝子変異を同定したことから学術的意義が大きいと考えられる。遺伝子変異の機能の一部まで明らかにしたことは、より発展的な研究にもつながる成果である。海綿状血管奇形には既存の治療方法では難治になる場合もあり新規治療法が求められていることから、本研究成果の社会的意義は大きいと考えられる。