一般口演
ゲノム医療と遺伝子治療 / 再生医療など
Genomic Medicine and Gene Therapy / Regenerative Medicine
座長：横田 隆徳（東京医科歯科大学） |
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| 2022年7月3日 9:00～9:15 沖縄コンベンションセンター 会議場B3・4 第6会場
4O06m1-01
アンチセンス核酸によるAMPA受容体関連神経毒性の解明
AMPA-receptor-related mechanism of neurotoxicity by antisense oligonucleotides via CSF-route
*吉岡 耕太郎(1)、Jia Chunyan(1)、Mon Su Su Lei(1)、勝山 真帆(1)、Yang Ying(1)、松林 泰毅(1)、田中 規恵(1)、永田 哲也(1)、横田 隆徳(1)
1. 東京医科歯科大学
*KOTARO YOSHIOKA(1), Chunyan Jia(1), Su Su Lei Mon(1), Maho Katsuyama(1), Ying Yang(1), Taiki Matsubayashi(1), Kie Tanaka(1), Tetsuya Nagata(1), Takanori Yokota(1)
1. Tokyo Medical and Dental University
Keyword: Antisense oligonucleotide, Neurotoxicity, AMPA receptor
Therapeutic oligonucleotides have been developed to treat intractable CNS diseases. One of best known antisense-oligonucleotide (ASO), nusinersen, is marketed in over 40 countries. In addition, patient-customized ASOs such as milasen have emerged as one of most promising modalities for ‘N of 1’ therapy targeting CNS diseases. However, ASOs causes severe and often lethal CNS-toxicity via injection to CSF space. Consequently, the CNS-toxicity is one of most challenging and urgent issues for those clinical development. Therefore, an evaluation of this neurotoxicity from a behavioral perspective is important to reveal symptomatic dysfunction of CNS and elucidate the underlying molecular mechanism. We here categorized and quantified the acute neurotoxicity of mice administered with toxic ASOs via intracerebroventricular injection by a behavioral analysis method including acute tolerability scoring system and open-field test. The toxic ASOs were found to reduce consciousness and locomotor function in mice in a dose-dependent manner. Mechanistically, we analyzed the role of ionotropic glutamate receptors, which can be inhibited by guanine nucleotide, in the ASO-neurotoxicity. An AMPA-receptor antagonist exaggerated the ASO-induced neurotoxicity, whereas an AMPA-receptor agonist mitigated the toxicity without altering knockdown efficacy of the ASOs. In contrast, NMDA receptor antagonist did not change the neurotoxicity. In an in vitro assay to evaluate intracellular calcium levels using rat primary cortical neurons, toxic ASOs reduced the calcium levels as well as the inhibitor of AMPA-receptor did. Based on our findings, we suggest that additional administration of an AMPAR agonist can mitigate ASO neurotoxicity without reducing the silencing efficacy of target genes, is a promising strategy to improve in vivo the therapeutic index of ASOs targeting the CNS. Because CNS toxicity of ASOs is one of their crucial limitations for clinical application, our findings could provide new insights to overcome the limitation and would lead to the development of novel strategies and technologies for targeting CNS diseases with ASOs.
| | 2022年7月3日 9:15～9:30 沖縄コンベンションセンター 会議場B3・4 第6会場
4O06m1-02
Epimedium flavonoids alleviates the demyelination and neurological disorders in mice exposed to Cuprizone
*Denglei Ma(1), lin li(1), Lan Zhang(1), yali li(1), weipeng wei(1)
1. Xuanwu Hospital, Capital Medical University
Keyword: Demyelination, Epimedium flavonoids, White matter lesion, Necroptosis
Introduction:Demyelination is found in several neurological diseases including multiple sclerosis (MS), cerebral small vascular disease (CSVD), and Alzheimer’s diseases (AD). Cuprizone induced toxic demyelinating model, characterized by the degeneration of oligodendrocytes, has been utilized to study white matter lesions. Epimedium flavonoids (EF) are the main ingredients extracted from Epimedium, a widely used traditional Chinese medicine for thousands of years. The aim of the present study was to investigate the effects and mechanisms of EF on Cuprizone-induced mouse model of demyelination.Methods:Female C57BL/6 mice were fed with chow containing 0.2 % Cuprizone. 3 weeks later the mice were treated with EF for 4 weeks. Y maze test, object recognition test and Tail suspension test were applied to test the behavioral performance. WM lesions were observed by MRI-diffusion tensor imaging, transmission electron microscopy, LFB staining and Oil red O staining. Oligodendrocytes were detected by immunohistochemistry. Western blot assay was used to protein expression in the brain of Cuprizone-mice to explain future mechanisms.Results:The results showed that EF significantly improved learning and memory impairments,alleviated the depressive behaviour and white matter lesions. Moreover, EF improved the ultra-structure of myelin fibers and increased the number of mature oligodendrocytes in the corpus callosum of the mice. Mechanistically, EF reduced the numbers of activted astrocytes and decreased the expression levels of receptor-interacting protein kinase-1 (RIPK1), mixed lineage kinase domain-like protein (MLKL) and p-MLKL in the corpus callosum of the mice. Conclusion:These results suggest that EF may improve cognitive impairment, depressive disorders and white matter lesion induced by Cuprizone. The possible mechanims might be related with promoting the differentiation and maturation of oligodendrocytes due to the effects of EF on inflammatory and necroptosis by inhibiting RIPK1/p-MLKL/MLKL pathway. We infer that EF might protect the mice against demyelination, which can be used as a potential agent for neurological diseases including MS, CSVD and AD. | | 2022年7月3日 9:30～9:45 沖縄コンベンションセンター 会議場B3・4 第6会場
4O06m1-03
左内包の神経膠腫と右後部島の構造に影響される統辞機能
Syntactic functions affected by both a glioma in the left internal capsule and structures in the right posterior insula
*金野 竜太(1,2)、村垣 善浩(3)、丸山 隆志(3)、田村 学(3)、田中 恭平(1)、小野 賢二郎(4)、酒井 邦嘉(1)
1. 東京大学大学院総合文化研究科相関基礎科学系、2. 昭和大学横浜市北部病院内科（神経）、3. 東京女子医科大学脳神経外科、4. 昭和大学医学部内科学講座脳神経内科学部門
*Ryuta Kinno(1,2), Yoshihiro Muragaki(3), Takashi Maruyama(3), Manabu Tamura(3), Kyohei Tanaka(1), Ono Kenjiro(4), Kuniyoshi Sakai(1)
1. Dept Basic Science, Grad Sch Arts and Sci, Univ of Tokyo, Tokyo, Japan, 2. Div Neurol, Dept Intern Med, Showa Univ Northern Yokohama Hosp, Yokohama, Japan, 3. Dept Neurosurg, Tokyo Women's Med Univ, Tokyo, Japan, 4. Div Neurol, Dept Med, Showa Univ Sch Med, Tokyo, Japan
Keyword: glioma, language, anatomical change, surface based morphometry
It has been demonstrated that a glioma causes agrammatism and affects functional connectivity within the syntax-related networks (Kinno et al., 2014, 2015). Here we clarified anatomical changes in the cerebral cortex induced by a glioma. The current study included 28 patients with a left hemispheric glioma (patient group) and 23 healthy participants (control group), who were all right-handed. The syntactic functions were assessed by a picture-sentence matching task, in which we tested six different sentence types: subject-initial active (e.g., A-ga B-o hiiteru), passive (e.g., B-ga A-ni hikareru), and potential (e.g., A-ni B-ga hiketeru) sentences, as well as object-scrambled active (e.g., B-o A-ga hiiteru), passive (e.g., B-ga A-ni hikareru), and potential (e.g., B-ga A-ni hiketeru) sentences. The participants judged whether the action depicted in a picture matched the meaning of the sentence. The MRI scans were conducted on a 3.0 T system (GE), and the effects of tumor locations on behavioral data were assessed by the ROI-based lesion-symptom mapping (RLSM). The MR image of a patient was first normalized and segmented according to the standard atlas. The patients were divided into two groups according to whether they did or did not have a glioma in each segmented area, and the behavioral data were then compared between these two groups by a t-test. Surface-based morphometry (SBM) was also performed using the CAT12 Toolbox to assess the cortical thickness (CT) and complexity (fractal dimension: FD). A factor analysis for the error rates revealed a two-factor structure, such that the factor 1 reflected the error rates of active and passive sentences, whereas the factor 2 reflected those of potential sentences. The RLSM for the factor scores showed that the patients with a glioma in the left internal capsule showed a significantly higher score for the factor 1 than those with a glioma in other regions (corrected p < .05). The SBM showed that the control group had significantly decreased CT in the right posterior insula, which was associated with the factor 2 (corrected p < .05). Consistently, the patient group had a significantly decreased CT and increased FD in the right posterior insula, which was associated with the factor 1. These findings suggest that a glioma in the particular tract, as well as structural variations even in the normal brain, affected syntactic functions. The left internal capsule may be important for the preserved syntactic functions. | | 2022年7月3日 9:45～10:00 沖縄コンベンションセンター 会議場B3・4 第6会場
4O06m1-04
Rock, paper, scissors – the effect of social defeat paradigm on human subjects stress response
*Eriko Matsumoto(1,2), Pavel Prosselkov(1)
1. Manai Institute of Science and Technology, Tokyo, Japan, 2. Hiroo Gakuen High school, Tokyo, Japan
Keyword: Competition , Stress, Social defeat paradigm
Competition is universal, existing in all areas of our lives from school, sports, and workplaces. It is taught from a young age, making competition almost an unconscious process. It can be immensely joyous and exciting, while also being very stressful and exhausting. The emotional responses gained from winning or losing differ widely depending on one’s mental and emotional states. Finding a correlation between one’s mental state and their performance in competitive situations could become tools for early detection and treatment of stress, especially for those who feel pressure under contest. Winning typically evokes feelings of euphoria and satisfaction that can help people gain a positive view of themselves, whereas losing may result in frustration and disappointment that can potentially lower self-esteem. Based on previous research, it was determined that increased stress correlates with greater emotional negativity. Also, the act of being competitive and striving to avoid inferiority are linked to anxiety and stress. Building on the concepts of the social defeat paradigm, a competitive situation is created with a game of rock-paper-scissors to assess cognitive bias (though confidence reports and optimistic-pessimistic bettings). Also, the subjects were later asked to answer questions related to the current situation caused by the COVID-19 pandemic to assess their emotional bias. The results are interpreted as factors affecting the scores (conditioning, age, gender, and nationality), and their interactions. | |
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