Elucidating Brain and Heart Pathophysiology of Mental Disorders through Multilayered Analysis: The Embodiment of the Diseasome

2023 Fiscal Year Final Research Report

• Project/Area Number: 20K20602
• Research Category: Grant-in-Aid for Challenging Research (Pioneering)
• Allocation Type: Multi-year Fund
• Review Section: Medium-sized Section 52:General internal medicine and related fields
• Research Institution: Nagoya University
• Principal Investigator: Ozaki Norio 名古屋大学, 医学系研究科, 特任教授 (40281480)
• Project Period (FY): 2020-07-30 – 2024-03-31
• Keywords: 22q11.2欠失 / 3q29欠失 / iPS細胞 / 精神疾患 / 心疾患

Outline of Final Research Achievements

In this study, we aimed to elucidate cardiac pathology using patient-derived iPS cells and model mice with genomic variants such as 22q11.2 deletion and 3q29 deletion, which are risk factors for both psychiatric and cardiac disorders.
Bulk RNA-seq analysis of cardiomyocytes derived from iPS cells from healthy controls and patients with 22q11.2 deletion (22qdel-PT) suggested Golgi and endoplasmic reticulum abnormalities in cardiomyocytes derived from 22qdel-PT. It has been reported that Golgi and endoplasmic reticulum abnormalities in the heart contribute to the development and progression of cardiac diseases such as heart failure and arrhythmia, and may be one of the causes of vulnerability in heart of 22qdel-PT. We have also shown that the endoplasmic reticulum stress response is abnormal in dopaminergic neurons derived from 22qdel-PT. These results suggest that endoplasmic reticulum abnormalities may be common in the pathological background of both heart and brain.

Free Research Field

精神医学

Academic Significance and Societal Importance of the Research Achievements

従来、精神疾患の病態解明研究においては、統合失調症等精神疾患患者は短命で、その死因として心臓死が多いことが示されているにも関わらず、脳病態の解明に専ら焦点づけられ、心臓病態と脳病態との関係性に関してはアプローチされることすら乏しかった。本研究により、精神疾患と心疾患双方のリスクである22q11.2欠失患者心筋細胞におけるゴルジ体および小胞体異常の存在が明らかとなったことは、精神疾患患者の心身両面における健康寿命延伸、22q11.2欠失患者の家族からの、「心臓に病気があっても安全に使える治療法の開発を」という思いの実現に繋がり得る成果である。