シンポジウム
44 異分野融合による精神神経疾患の新規治療標的に基づいた創薬研究
44 Drug discovery based on novel therapeutic target to neuropsychiatric disorders in interdisciplinary research
座長：衣斐 大祐（名城大学薬学部薬品作用学研究室）・毛利 彰宏（藤田医科大学 医療科学部 レギュラトリーサイエンス） |
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| 2022年6月30日 9:05～9:25 沖縄コンベンションセンター 会議場B1 第3会場
1S03m-01
オミックス技術による統合失調症の病態関連分子の探索とバイオマーカー開発
Identification of molecules involved in the pathophysiology of schizophrenia using omics technology and development of biomarkers
*吉見 陽(1)
1. 名城大学薬学部
*Akira Yoshimi(1)
1. Fac Pharm, Meijo Univ, Nagoya, Japan
Keyword: schizophrenia, biomarker, proteome, lymphoblastoid cell line
Although a number of studies have identified several convincing candidate genes or molecules, the pathophysiology of schizophrenia has not been completely elucidated. Therapeutic optimization based on pathophysiology should be performed as early as possible to improve functional outcomes and prognosis; to detect useful biomarkers for schizophrenia, which reflect pathophysiology and can be utilized for timely diagnosis and effective therapy. To elucidate pathophysiology and search for biomarkers, we have conducted research using omics technologies (next-generation sequencing, microarray, and mass spectrometry). Here, I would like to talk about the proteome analysis of lymphoblastoid cell lines derived from patients with schizophrenia. We employed fluorescence two-dimensional differential gel electrophoresis and differentially expressed proteins (DEPs) were sequenced by liquid chromatography tandem-mass spectrometry. DEPs were confirmed by western blotting and multivariate logistic regression analysis was performed to identify an optimal combination of biomarkers to create a prediction model for schizophrenia. Among the eight candidate proteins (HSPA4L, MX1, GLRX3, UROD, MAPRE1, TBCB, IGHM, and GART), we successfully constructed logistic regression models comprised of 4- and 6-markers with good discriminative ability between SCZ and CON. In both WB and gene expression analysis of LCL, MX1 showed reproducibly significant associations. Moreover, Mx1 and its related proinflamatory genes (Mx2, Il1b, and Tnf) were also up-regulated in poly I:C-treated mice. Differentially expressed proteins might be associated with molecular pathophysiology of SCZ, including dysregulation of immunological reactions and potentially provide diagnostic and prognostic biomarkers. | | 2022年6月30日 9:25～9:45 沖縄コンベンションセンター 会議場B1 第3会場
1S03m-02
22q11.2欠失症候群患者の脳内分子・細胞病態としてのPERK機能不全とその意義
PERK dysfunction as a molecular and cellular pathophysiology in the brain of patients with 22q11.2 deletion syndrome and its significance
*有岡 祐子(1,2)
1. 名古屋大学医学部附属病院、2. 名古屋大学大学院医学系研究科精神医学分野
*Yuko Arioka(1,2)
1. Nagoya Univ Hosp, Aichi, Japan, 2. Dept Psych, Grad Sch Med, Nagoya Univ, Aichi, Japan
Keyword: 22q11.2 deletion, iPS cell
Genetic and clinical studies have identified that people with 22q11.2 deletions (22q11.2DS) are at an extremely high risk of neuropsychiatric disorders, such as schizophrenia and Parkinson’s disease. Many efforts have been taken to determine the 22q11.2DS-related brain pathology at the cellular and molecular levels. However, despite of the high risk of Parkinson’s disease, most studies have mainly focused on the cortex and hippocampus and not on the midbrain. To this end, our study aimed to use patient-derived induced pluripotent stem cells (iPSCs), which focuses on dopaminergic neurons. In the present study, we provide compelling evidence that protein kinase R-like endoplasmic reticulum kinase (PERK) is a target protein underlying 22q11.2DS-related brain pathology in dopaminergic neurons. We showed (1) that “Protein processing in the endoplasmic reticulum (ER)” is the most altered pathway in 22q11.2DS patient-derived dopaminergic neurons and (2) a severe defect in PERK protein expression in patient’s iPSC-derived dopaminergic neurons, which was also observed in the midbrain of 22q11.DS model mouse. In addition, we verified that (3) PERK dysfunction causes characteristic phenotypes, such as low tolerance to ER stress and abnormal F-actin dynamics, in patient-derived dopaminergic neurons. Finally, we revealed that (4) DGCR14, a gene located in chromosome 22q11.2, was associated with a decrease in PERK expression. Because PERK has been recently reported to be a multi-player in neuronal function from actin cytoskeleton to neural wiring, PERK dysfunction as an underlying mechanism for the pathogenesis of neuropsychiatric disorders in 22q11.2DS shows great potential. | | 2022年6月30日 9:45～10:01 沖縄コンベンションセンター 会議場B1 第3会場
1S03m-03
外側中隔核におけるセロトニン5-HT2A受容体のストレス関連疾患に対する治療標的としての有用性
Validity of serotonin 5-HT2A receptor in the lateral septum as a therapeutic target of stress-related disorders
*衣斐 大祐(1)
1. 名城大学薬学部薬品作用学研究室
*Daisuke Ibi(1)
1. Dept Chem Pharmacol, Meijo Univ, Nagoya, Japan
Keyword: Psychedelics , Depression, Serotonin 5-HT2A receptor, Lateral septum
Recently, FDA approved psilocybin, the psychoactive substance found in the magic mushroom, as a “breakthrough therapy” for depression. Serotonergic psychedelics such as psilocybin and LSD have hallucinatory effect through stimulation of the cortical serotonin 5-HT2A receptor (5-HT2A). We have already demonstrated the therapeutic effect of serotonergic psychedelics on impairments of emotion-related behaviors in a mouse model of depression chronically exposed with chronic unpredictable mild stress (CUMS) in early life. These motivated us to investigate the neural bases underlying antidepressant effect of serotonergic psychedelics through 5-HT2A stimulation in mice. We found that acute treatment of serotonergic psychedelics such as DOI and psilocin, an active metabolite of psilocybin, decreased immobility time in the forced-swim test (FST), which was absent in mice with knockdown of Htr2a (5-HT2A gene) in the lateral septum (LS) by AAV-delivered shRNA, suggesting that serotonergic psychedelics has antidepressant-like effect through stimulation of 5-HT2A in the LS. Further, we found that 5-HT2A was abundantly expressed in GABAergic neurons in the LS, which projects to the anterior hypothalamus (AHA) in mice. Therefore, we next investigated the role of 5-HT2A-positive neurons in the LS projecting to AHA in antidepressant effect of psilocin. Selective optogenetic inhibition of 5-HT2A-positive neurons in the LS projecting to AHA eliminated the antidepressant-like effect of psilocin in mice. Moreover, selective chemogenetic activation of 5-HT2A-positive neurons in the LS induced antidepressant-like effect in mice. Also, such effect of psilocin tended to diminish in mice with microinjection of bicuculline, an antagonist of GABAA receptor, into the AHA. These results suggest that 5-HT2A-positive GABAergic neurons in LS projecting to AHA contributes to antidepressant effect of serotonergic psychedelics. In addition, in this symposium, I would like to introduce the significance of 5-HT2A in the cerebral cortex in antidepressant- and hallucination-like behaviors following treatment of serotonergic psychedelics in mice. | | 2022年6月30日 10:01～10:17 沖縄コンベンションセンター 会議場B1 第3会場
1S03m-04
精神疾患におけるトリプトファン代謝の変容に注目したバイオマーカー・治療薬戦略
Development of biomarker and therapeutic agents for psychiatric disorders focusing on alteration of tryptophan metabolism
*毛利 彰宏(1,4)、國澤 和生(1)、齋藤 邦明(2,4)、鍋島 俊隆(3,4)
1. 藤田医科大学大学院保健学研究科レギュラトリーサイエンス、2. 藤田医科大学大学院保健学研究科病態制御解析学、3. 藤田医科大学大学院保健学研究科先進診断システム探索、4. 特定非営利活動法人 医薬品適正使用推進機構|
*Akihiro Mouri(1,4), Kazuo Kunisawa(1), Kuniaki Saito(2,4), Toshitaka Nabeshima(3,4)
1. Department of Regulatory Science for Evaluation and Development of Pharmaceuticals and Devices, Fujita Health University Graduate School of Health Sciences, 2. Department of Diseases Control and Prevention, Fujita Health University Graduate School of Health Sciences, 3. Advanced Diagnostic System Research Laboratory, Fujita Health University Graduate School of Health Sciences, 4. Japanese Drug Organization of Appropriate Use and Research
Keyword: Depression, Animal model, Tryptophan, Biomarker
Major depressive disorder (MDD) is a leading cause of disability which gives rise to profound social and economic burdens. Dysregulation of the immune system is closely involved in the pathogenesis of MDD. Tryptophan metabolism has attracted considerable attention due to its influence on the onset of MDD via induction of inflammation. In this symposium, we will introduce the changes in blood levels of tryptophan metabolites in MDD high risk subjects and pregants for development of biomarker for MDD. Chronic stress is a significant risk factor in the development of MDD. We will introduce the changes in brain levels of tryptophan metabolites in MDD animal models made by subjecting chronic stress and deliting tryptophan metabolite enzyames for development of therapeutic agents for MDD. | | 2022年6月30日 10:17～10:37 沖縄コンベンションセンター 会議場B1 第3会場
1S03m-05
創薬に資するGPCRの構造生物学
Structural biology of GPCRs for drug discovery
*寿野 良二(1)
1. 関西医科大学
*Ryoji Suno(1)
1. Kansai Medical University
Keyword: GPCR, X-ray crystallography, Cryo-EM SPA, signal transduction
G-protein-coupled receptors (GPCRs) are known to be an important drug target, accounting for about 30% of the drugs currently on the market. Drug development for GPCRs is mainly done by screening for signal activity using an extensive compound library. With the structural information of GPCRs, it is possible to rationally design compounds suitable for the binding sites. Furthermore, drug design by computerized in silico screening based on the structural information has been reported. To date, the speed of the structural analysis of GPCRs has been dramatically accelerated by the improvement of various structural analysis technologies and protein production technologies, and the rapid development of drugs based on the structural information of GPCRs is expected. We have conducted structural analysis of various GPCRs such as orexin 2 receptor (OX2R), muscarinic M2 receptor, and prostaglandin receptors by X-ray crystallography and cryo-EM single particle analysis (Cryo-EM SPA). Although most of the structures of inactive GPCRs have been determined by X-ray crystallography, recent analysis using Cryo-EM has revealed that the structures of GPCRs with signaling factors including G-proteins are different. However, recent Cryo-EM analysis has elucidated the structure of the active complex with signal transducers including G-proteins and has revealed the molecular mechanism in more detail. In particular, clarifying the differences in signaling mechanisms between G-proteins and non-G-proteins is expected to lead to the reduction of side effects of drugs. In this symposium, I would like to discuss the details of the signaling mechanism elucidated through the structural analysis of GPCRs in various reaction states including our research results, and the possibility of drug discovery based on the structural information. | | 2022年6月30日 10:37～10:57 沖縄コンベンションセンター 会議場B1 第3会場
1S03m-06
オレキシン受容体を標的としたアカデミア創薬研究
Drug Discovery Research in Academia Targeting Orexin Receptors
*沓村 憲樹(1)
1. 筑波大学
*Noriki Kutsumura(1)
1. University of Tsukuba
Keyword: orexin, drug discovery, organic synthetic chemistry
Orexins A and B are neuropeptides that were identified as endogenous ligands for orphan G protein-coupled receptors by Yanagisawa, Sakurai, and colleagues in 1998. Orexins regulate a variety of physiological effects by binding to two GPCR subtypes (orexin 1 and orexin 2 receptors). One of the most important physiological effects is the regulation of sleep and wakefulness. Suvorexant, developed by Merck in 2014, and lemborexant, developed by Eisai Co., Ltd. in 2020, are both orexin 1 and 2 receptor dual antagonists, and both have been approved for the treatment of insomnia. In addition, orexin 2 receptor selective agonists have recently been attracting attention as a treatment for narcolepsy, a type of hypersomnia. At the current stage of writing this abstract, several promising orexin 2 receptor selective agonists have entered clinical trials.
We, in the Drug Discovery Laboratory, have been studying to develop the orexin ligands with collaboration to Yanagisawa, who discovered orexin, et al. In 2015, we developed the world's first non-peptidic orexin 2 receptor selective agonist, YNT-185. Due to its high-water solubility and blood-brain barrier permeability, the drug showed clear in vivo efficacy. Based on the molecular structure of YNT-185, second- and third-generation orexin 2 receptor selective agonists are also being developed. Also in 2017, we developed YNT-1310, an orexin 1 receptor super-selective antagonist with a morphinan skeleton. We are still conducting detailed structure-activity relationship studies on the characteristic skeleton of morphinan structures and their orexin 1 receptor antagonist activity. Our ultimate goal is to develop a drug to treat narcolepsy, but at the same time, detailed orexin ligand-based studies would help to elucidate more detailed function of the orexin system, especially the function of the orexin 1 receptor itself and the orexin 2 receptor itself.
In this presentation, I will give an overview of our orexin drug discovery research and my personal impressions of drug discovery research in academia, from the perspective of a university faculty member with a background in synthetic organic chemistry. | |
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