日本人におけるパニック症のゲノム・エピゲノムワイド関連解析

学位の種別: 課程博士審査委員会委員 : （主査）東京大学教授 神馬 征峰, 東京大学准教授 渡邊 洋一, 東京大学教授 岩坪 威, 東京大学准教授 田中 輝幸, 東京大学准教授 垣内 千尋University of Tokyo(東京大学

The Design of Learning Environment and Learning Support for Higher Education in Taiwan

本論文は，JSPS科研費JP19K03040、JP19H01710の助成を受けている

Polymorphism Located between CPT1B and CHKB, and HLA-DRB1*1501-DQB1*0602 Haplotype Confer Susceptibility to CNS Hypersomnias (Essential Hypersomnia)

Background: SNP rs5770917 located between CPT1B and CHKB, and HLA-DRB1*1501-DQB1*0602 haplotype were previously identified as susceptibility loci for narcolepsy with cataplexy. This study was conducted in order to investigate whether these genetic markers are associated with Japanese CNS hypersomnias (essential hypersomnia: EHS) other than narcolepsy with cataplexy. Principal Findings: EHS was significantly associated with SNP rs5770917 (Pallele = 3.6610 23; OR = 1.56; 95 % c.i.: 1.12–2.15) and HLA-DRB1*1501-DQB1*0602 haplotype (Ppositivity = 9.2610 211; OR = 3.97; 95 % c.i.: 2.55–6.19). No interaction between the two markers (SNP rs5770917 and HLA-DRB1*1501-DQB1*0602 haplotype) was observed in EHS. Conclusion: CPT1B, CHKB and HLA are candidates for susceptibility to CNS hypersomnias (EHS), as well as narcolepsy with cataplexy

Narcolepsy risk loci outline role of T cell autoimmunity and infectious triggers in narcolepsy

Narcolepsy has genetic and environmental risk factors, but the specific genetic risk loci and interaction with environmental triggers are not well understood. Here, the authors identify genetic loci for narcolepsy, suggesting infection as a trigger and dendritic and helper T cell involvement. Narcolepsy type 1 (NT1) is caused by a loss of hypocretin/orexin transmission. Risk factors include pandemic 2009 H1N1 influenza A infection and immunization with Pandemrix (R). Here, we dissect disease mechanisms and interactions with environmental triggers in a multi-ethnic sample of 6,073 cases and 84,856 controls. We fine-mapped GWAS signals within HLA (DQ0602, DQB1*03:01 and DPB1*04:02) and discovered seven novel associations (CD207, NAB1, IKZF4-ERBB3, CTSC, DENND1B, SIRPG, PRF1). Significant signals at TRA and DQB1*06:02 loci were found in 245 vaccination-related cases, who also shared polygenic risk. T cell receptor associations in NT1 modulated TRAJ*24, TRAJ*28 and TRBV*4-2 chain-usage. Partitioned heritability and immune cell enrichment analyses found genetic signals to be driven by dendritic and helper T cells. Lastly comorbidity analysis using data from FinnGen, suggests shared effects between NT1 and other autoimmune diseases. NT1 genetic variants shape autoimmunity and response to environmental triggers, including influenza A infection and immunization with Pandemrix (R)

Spatial distribution and risk factors of Schistosoma haematobium and hookworm infections among schoolchildren in Kwale, Kenya

Background: Large-scale schistosomiasis control programs are implemented in regions with diverse social and economic environments. A key epidemiological feature of schistosomiasis is its small-scale heterogeneity. Locally profiling disease dynamics including risk factors associated with its transmission is essential for designing appropriate control programs. To determine spatial distribution of schistosomiasis and its drivers, we examined schoolchildren in Kwale, Kenya. Methodology/Principal findings: We conducted a cross-sectional study of 368 schoolchildren from six primary schools. Soil-transmitted helminths and Schistosoma mansoni eggs in stool were evaluated by the Kato-Katz method. We measured the intensity of Schistosoma haematobium infection by urine filtration. The geometrical mean intensity of S. haematobium was 3.1 eggs/10 ml urine (school range, 1.4?9.2). The hookworm geometric mean intensity was 3.2 eggs/g feces (school range, 0?17.4). Heterogeneity in the intensity of S. haematobium and hookworm infections was evident in the study area. To identify factors associated with the intensity of helminth infections, we utilized negative binomial generalized linear mixed models. The intensity of S. haematobium infection was associated with religion and socioeconomic status (SES), while that of hookworm infection was related to SES, sex, distance to river and history of anthelmintic treatment. Conclusions/Significance: Both S. haematobium and hookworm infections showed micro-geographical heterogeneities in this Kwale community. To confirm and explain our observation of high S. haematobium risk among Muslims, further extensive investigations are necessary. The observed small scale clustering of the S. haematobium and hookworm infections might imply less uniform strategies even at finer scale for efficient utilization of limited resources

Degradation of ionic liquids by a UV/H2O2 process and CMCase from novel ionic liquid-tolerant alkaliphilic Nocardiopsis sp. SSC4

We demonstrated the degradation of two ionic liquids (1-butyl-3-methylimidazolium chloride, [BMIM]Cl, and 1-ethylpyridinium bromide, [EtPy]Br) that are useful for the solubilization of wood components. [BMIM]+ and [EtPy]+ were detected by thin-layer chromatography (TLC) and electrospray ionization–mass spectrometry (ESI-MS). [BMIM]+ was harder to degrade than [EtPy]+. Ultraviolet (UV) irradiation with 0.2% (v/v) H2O2 for 16 h degraded 1 mmol/L [BMIM]+, whereas UV irradiation alone degraded 1 mmol/L [EtPy]+. Additionally, we isolated an ionic liquid-tolerant alkaliphilic actinomycete, Nocardiopsis sp. SSC4. Strain SSC4 produced carboxymethylcellulase (CMCase) in the presence of 1.0% (v/v, 48.1 mmol/L) 1-ethyl-3-methylimidazolium trifluoromethanesulphonate ([EMIM]CF3SO3), which is useful for the extraction of cellulose-rich materials from wood. In the case of strain SSC4, CMCase was inducibly synthesized by more than 0.5% CMC. The addition of 0%–1.0% tryptone or 0%–2.0% yeast extract decreased the CMCase activity in a concentration-dependent manner. After cultivation of strain SSC4 with 1.0% (w/v) CMC medium (pH 9.0) for 48 h at 37 °C, the culture supernatant exhibited CMCase activity at 0.03 U/mg. The optimum reaction temperature of CMCase was 45 °C. CMCase was stable up to 37 °C for 20 h incubation. The degradation characteristics of [BMIM]+ and [EtPy]+ and the activity of CMCase in the presence of [EMIM]CF3SO3 may be useful for the development of a bioconversion system for biomass resources

Accumulation of the myosin-II-spectrin complex plays a positive role in apical extrusion of Src-transformed epithelial cells

At the initial stage of carcinogenesis, transformation occurs in single cells within the epithelium. Recent studies have revealed that the newly emerging transformed cells are often apically eliminated from epithelial tissues. However, the underlying molecular mechanisms of this cancer preventive phenomenon still remain elusive. In this study, we first demonstrate that myosin-II accumulates in Src-transformed cells when they are surrounded by normal epithelial cells. Knock-down of the heavy chains of myosin-II substantially diminishes apical extrusion of Src cells, suggesting that accumulated myosin-II positively regulates the apical elimination of transformed cells. Furthermore, we have identified β-spectrin as a myosin-II-binding protein under the coculture of normal and Src-transformed epithelial cells. β-spectrin is also accumulated in Src cells that are surrounded by normal cells, and the β-spectrin accumulation is regulated by myosin-II. Moreover, knock-down of β-spectrin significantly suppresses apical extrusion of Src cells. Collectively, these results indicate that accumulation of the myosin-II-spectrin complex plays a positive role in apical extrusion of Src-transformed epithelial cells. Further elucidation of the molecular mechanisms of apical extrusion would lead to the establishment of a novel type of cancer preventive medicine

Plectin is a novel regulator for apical extrusion of RasV12-transformed cells

Several lines of evidence have revealed that newly emerging transformed cells are often eliminated from the epithelium, though the underlying molecular mechanisms of this cancer preventive phenomenon still remain elusive. In this study, using mammalian cell culture systems we have identified plectin, a versatile cytoskeletal linker protein, as a novel regulator for apical extrusion of RasV12-transformed cells. Plectin is accumulated in RasV12 cells when they are surrounded by normal epithelial cells. Similarly, cytoskeletal proteins tubulin, keratin, and Epithelial Protein Lost In Neoplasm (EPLIN) are also accumulated in the transformed cells surrounded by normal cells. Knockdown or functional disruption of one of these molecules diminishes the accumulation of the others, indicating that the accumulation process of the individual protein mutually depends on each other. Furthermore, plectin-knockdown attenuates caveolin-1 (Cav-1) enrichment and PKA activity in RasV12 cells and profoundly suppresses the apical extrusion. These results indicate that the plectin-microtubules-EPLIN complex positively regulates apical elimination of RasV12-transformed cells from the epithelium in a coordinated fashion. Further development of this study would open a new avenue for cancer preventive medicine