Elucidation of molecular mechanisms of neuromuscular junction formations in physiology and pathology

2022 Fiscal Year Final Research Report

• Project/Area Number: 20H03561
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 51030:Pathophysiologic neuroscience-related
• Research Institution: Nagoya University
• Principal Investigator: Ohno Kinji 名古屋大学, 医学系研究科, 教授 (80397455)
• Co-Investigator(Kenkyū-buntansha): 増田 章男 名古屋大学, 医学系研究科, 准教授 (10343203) ; 大河原 美静 名古屋大学, 医学系研究科, 特任准教授 (80589606)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Keywords: 神経筋接合部 / 先天性筋無力症候群

Outline of Final Research Achievements

Specific AIMs of the current project were to elucidate the physiological molecular structures of the neuromuscular junction (NMJ) and their aberrations in congenital myasthenic syndromes (CMS) to develop novel therapeutic modalities for CMS. We identified three novel secreted molecules (Rspo2, Fgf18, and Ctgf) and their cognate receptors (Lgr5, Fgfr2, Lrp4) that are essential for the formation and the maintenance of NMJ. We identified and functionally characterized mutations in the CHRND, CHRNG, and DOK7 genes in Japanese patients with CMS. In addition, we generated in vitro NMJ and found that anti-epileptic and anti-parkinsonian drug, zonisamide, induces the clustering of acetylcholine receptors by upregulating neuregulin. We also published an extensive review article on CMS by citing as many as 442 references.

Free Research Field

神経遺伝情報学分野

Academic Significance and Societal Importance of the Research Achievements

分子病態解析を含めたCMS研究拠点は、アメリカ3拠点(Professors. Andrew G. Engel, Ricard A. Maselli, Christopher M. Gomez)、カナダ1拠点(Prof. Hanns Lochmuller)、イギリス1拠点(Prof. David Beeson)、フランス1拠点(Prof. Sophie Nicole)があり、研究代表者らはこれらの拠点と連携してCMS研究を行っている。CMSは未診断・誤診断のことが多く診断確定・病態機構解明・治療法開発が求められている。