大腸杯細胞の最終分化における小胞体ストレスセンサーOASISの役割

広島大学(Hiroshima University)博士(医学)Doctor of Philosophy in Medical Sciencedoctora

EGFR阻害薬は表皮ブドウ球菌によるβディフェンシンの発現を選択的に抑制する

BACKGROUND: Epidermal growth factor receptor inhibitors (EGFRIs) have developed as one of the potential treatment options for various kinds of cancers. Although a variety of dermatological adverse reactions such as follicular acneiform eruptions is commonly encountered, the mechanism of the reactions remains unclear. OBJECTIVES: We investigated the effects of EGFRIs on the expression of human β-defensins against staphylococci to study the pathomechanism of cutaneous adverse reactions caused by EGFRIs. METHODS: We investigated the expressions of human β-defensins 1, 2, and 3 (hBD1, 2, and 3) from staphylococci-stimulated normal human epidermal keratinocytes (NHEKs) cultured with or without the effects of two EGFRIs, gefitinib and erlotinib. We stimulated NHEKs with the supernatant of Staphylococcus aureus (S. aureus) and S. epidermidis and the live staphylococci. We measured hBDs in the culture supernatants of NHEKs by enzyme-linked immunosorbent assay (ELISA). RESULTS: EGFRIs did not suppress the expressions of hBD1 and 3 induced by S. aureus. In contrast, EGFRIs suppressed the expressions of hBD2 and 3 induced by S. epidermidis. CONCLUSION: EGFRIs may cause cutaneous adverse effects through selectively perturbing innate immune responses induced by commensal and pathogenic bacteria.博士（医学）・乙第1423号・平成30年11月30日Copyright © 2014 Elsevier Ireland Ltd. All rights reserved

Obesity-induced endoplasmic reticulum stress causes chronic inflammation in adipose tissue

Adipose tissue plays a central role in maintaining metabolic homeostasis under normal conditions. Metabolic diseases such as obesity and type 2 diabetes are often accompanied by chronic inflammation and adipose tissue dysfunction. In this study, we observed that endoplasmic reticulum (ER) stress and the inflammatory response occurred in adipose tissue of mice fed a high-fat diet for a period of 16 weeks. After 16 weeks of feeding, ER stress markers increased and chronic inflammation occurred in adipose tissue. We found that ER stress is induced by free fatty acid (FFA)-mediated reactive oxygen species (ROS) generation and up-regulated gene expression of inflammatory cytokines in 3T3-L1 adipocytes. Oral administration to obese mice of chemical chaperons, which alleviate ER stress, improved chronic inflammation in adipose tissue, followed by the suppression of increased body weight and improved insulin signaling. These results indicate that ER stress plays important pathophysiological roles in obesity-induced adipose tissue dysfunction.This work was partly supported by grants from the Japan Society for the Promotion of Science KAKENHI (#22020030, #22800049), Sumitomo Foundation, Mochida Memorial Foundation for Medical and Pharmaceutical Research, Astellas Foundation for Research on Metabolic Disorders, Takeda Science Foundation, The Pharmacological Research Foundation Tokyo, Daiichi-Sankyo Foundation of Life Science, and The Naito Foundation

ブドウ球菌の表皮ケラチノサイトからの選択的抗菌ペプチドの誘導

Staphylococcus aureus (S. aureus) is one of the most clinically important inflammation-inducing pathogens, while Staphylococcus epidermidis (S. epidermidis) is nonpathogenic and hardly causes inflammation on skin. β-defensins, antimicrobial peptides, are secreted from keratinocytes constitutively or upon induction by various microorganisms. However, the difference between S. aureus and S. epidermidis is still unclear in terms of their influences on the production of β-defensins. In this study, we focused on the influences of S. aureus and S. epidermidis on the keratinocyte innate immune response. Pathogenic S. aureus mainly induced human β-defensin (hBD) 1 and hBD3, but not hBD2, and nonpathogenic S. epidermidis mainly induced hBD2 from human keratinocytes. Molecular weight fractions of >10 kDa prepared from S. aureus supernatants induced the production of hBD1 and hBD3. On the other hand, molecular weight fraction of >100 kDa prepared from S. epidermidis supernatants induced the production of hBD2.Furthermore, the secreted products of S. epidermidis used the toll-like receptor (TLR) 2 pathway in the induction of hBD2 production. The secreted products of S. aureus and S. epidermidis differentially induced subtypes of hBD through different receptors, which may be associated with the difference in virulence between these two bacteria.博士（医学）・甲第643号・平成28年3月15日Copyright © 2012 Elsevier Ltd. All rights reserved

DIHS/DRESS患者における血清中HHV6B microRNAの変化

博士（医学）・甲第699号・平成31年3月15日Copyright © 2018. Acta Dermato-Venereologica. All rights reserved.This is an open access article under the CC BY-NC license(http://creativecommons.org/licenses/by-nc/4.0/)

Multidimensional analysis and therapeutic development using patient iPSC-derived disease models of Wolfram syndrome

Wolfram syndrome is a rare genetic disorder largely caused by pathogenic variants in the WFS1 gene and manifested by diabetes mellitus, optic nerve atrophy, and progressive neurodegeneration. Recent genetic and clinical findings have revealed Wolfram syndrome as a spectrum disorder. Therefore, a genotype-phenotype correlation analysis is needed for diagnosis and therapeutic development. Here, we focus on the WFS1 c.1672C\u3eT, p.R558C variant, which is highly prevalent in the Ashkenazi Jewish population. Clinical investigation indicated that patients carrying the homozygous WFS1 c.1672C\u3eT, p.R558C variant showed mild forms of Wolfram syndrome phenotypes. Expression of WFS1 p.R558C was more stable compared with the other known recessive pathogenic variants associated with Wolfram syndrome. Human induced pluripotent stem cell-derived (iPSC-derived) islets (SC-islets) homozygous for WFS1 c.1672C\u3eT variant recapitulated genotype-related Wolfram syndrome phenotypes. Enhancing residual WFS1 function through a combination treatment of chemical chaperones mitigated detrimental effects caused by the WFS1 c.1672C\u3eT, p.R558C variant and increased insulin secretion in SC-islets. Thus, the WFS1 c.1672C\u3eT, p.R558C variant causes a mild form of Wolfram syndrome phenotypes, which can be remitted with a combination treatment of chemical chaperones. We demonstrate that our patient iPSC-derived disease model provides a valuable platform for further genotype-phenotype analysis and therapeutic development for Wolfram syndrome

Unfolded protein response, activated by OASIS family transcription factors, promotes astrocyte differentiation

OASIS is a member of the CREB/ATF family of transcription factors and modulates cell- or tissue-specific unfolded protein response signalling. Here we show that this modulation has a critical role in the differentiation of neural precursor cells into astrocytes. Cerebral cortices of mice specifically deficient in OASIS (Oasis−/−) contain fewer astrocytes and more neural precursor cells than those of wild-type mice during embryonic development. Furthermore, astrocyte differentiation is delayed in primary cultured Oasis−/− neural precursor cells. The transcription factor Gcm1, which is necessary for astrocyte differentiation in Drosophila, is revealed to be a target of OASIS. Introduction of Gcm1 into Oasis−/− neural precursor cells improves the delayed differentiation of neural precursor cells into astrocytes by accelerating demethylation of the Gfap promoter. Gcm1 expression is temporally controlled by the unfolded protein response through interactions between OASIS family members during astrocyte differentiation. Taken together, our findings demonstrate a novel mechanism by which OASIS and its associated family members are modulated by the unfolded protein response to finely control astrocyte differentiation.This work was partly supported by grants from the Japan Society for the Promotion of Science KAKENHI (#22020030, #22800049), Sumitomo Foundation, Mochida Memorial Foundation for Medical and Pharmaceutical Research, Astellas Foundation for Research on Metabolic Disorders, Takeda Science Foundation, The Pharmacological Research Foundation Tokyo, Daiichi-Sankyo Foundation of Life Science, The Naito Foundation, Senri Life Science Foundation, Hokuto Foundation for Bioscience, and The Japan Prize Foundation