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研究代表者 多久和典子
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研究代表者 多久和典子
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論文
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Zhao, Juanjuan ; Okamoto, Yasuo ; Asano, Yuya ; Ishimaru, Kazuhiro ; Aki, Sho ; Yoshioka, Kazuaki ; Takuwa, Noriko ; Wada, Takashi ; Inagaki, Yutaka ; Takahashi, Chiaki ; Nishiuchi, Takumi ; Takuwa, Yoh ; 安藝, 翔 ; 吉岡, 和晃 ; 多久和, 典子 ; 和田, 隆志 ; 髙橋, 智聡 ; 西内, 巧 ; 多久和, 陽
概要:
金沢大学医薬保健研究域医学系<br />Idiopathic pulmonary fibrosis is a devastating disease with poor prognosis. The pathogenic role of t
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he lysophospholipid mediator sphingosine-1-phosphate and its receptor S1PR2 in lung fibrosis is unknown. We show here that genetic deletion of S1pr2 strikingly attenuated lung fibrosis induced by repeated injections of bleomycin in mice. We observed by using S1pr2 LacZ/+ mice that S1PR2 was expressed in alveolar macrophages, vascular endothelial cells and alveolar epithelial cells in the lung and that S1PR2-expressing cells accumulated in the fibrotic legions. Bone marrow chimera experiments suggested that S1PR2 in bone marrow–derived cells contributes to the development of lung fibrosis. Depletion of macrophages greatly attenuated lung fibrosis. Bleomycin administration stimulated the mRNA expression of the profibrotic cytokines IL-13 and IL-4 and the M2 markers including arginase 1, Fizz1/Retnla, Ccl17 and Ccl24 in cells collected from broncho-alveolar lavage fluids (BALF), and S1pr2 deletion markedly diminished the stimulated expression of these genes. BALF cells from bleomycin–administered wild-type mice showed a marked increase in phosphorylation of STAT6, a transcription factor which is activated downstream of IL-13, compared with saline–administered wild-type mice. Interestingly, in bleomycin–adminis-tered S1pr2 -/- mice, STAT6 phosphorylation in BALF cells was substantially diminished compared with wild-type mice. Finally, pharmacological S1PR2 blockade in S1pr2 +/+ mice alleviated bleomycin–induced lung fibrosis. Thus, S1PR2 facilitates lung fibrosis through the mechanisms involving augmentation of IL-13 expression and its signaling in BALF cells, and represents a novel target for treating lung fibrosis. © 2018 Zhao et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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Pham, Hoa Q. ; Yoshioka, Kazuaki ; Mohri, Hiromi ; Nakata, Hiroki ; Aki, Sho ; Ishimaru, Kazuhiro ; Takuwa, Noriko ; Takuwa, Yoh ; 吉岡, 和晃 ; 仲田, 浩規 ; 安藝, 翔 ; 多久和, 典子 ; 多久和, 陽
概要:
金沢大学医薬保健研究域医学系<br />Phosphatidylinositol 3-phosphate (PI(3)P) is the predominant phosphoinositide species in early endos
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omes and autophagosomes, in which PI(3)P dictates traffic of these organelles. Phosphoinositide levels are tightly regulated by lipid-kinases and -phosphatases; however, a phosphatase that converts PI(3)P back to phosphatidylinositol in the endosomal and autophagosomal compartments is not fully understood. We investigated the subcellular distribution and functions of myotubularin-related protein-4 (MTMR4), which is distinct among other MTMRs in that it possesses a PI(3)P-binding FYVE domain, in lung alveolar epithelium-derived A549 cells. MTMR4 was localized mainly in late endosomes and autophagosomes. MTMR4 knockdown markedly suppressed the motility, fusion, and fission of PI(3)P-enriched structures, resulting in decreases in late endosomes, autophagosomes, and lysosomes, and enlargement of PI(3)P-enriched early and late endosomes. In amino acid- and serum-starved cells, MTMR4 knockdown decreased both autophagosomes and autolysosomes and markedly increased PI(3)P-containing autophagosomes and late endosomes, suggesting that the fusion with lysosomes of autophagosomes and late endosomes might be impaired. Notably, MTMR4 knockdown inhibited the nuclear translocation of starvation stress responsive transcription factor-EB (TFEB) with reduced expression of lysosome-related genes in starved cells. These findings indicate that MTMR4 is essential for the integrity of endocytic and autophagic pathways. © 2018 Molecular Biology Society of Japan and John Wiley & Sons Australia, Ltd.<br />Embargo Period 12 months
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Aung, Khin Thuzar ; Yoshioka, Kazuaki ; Aki, Sho ; Ishimaru, Kazuhiro ; Takuwa, Noriko ; Takuwa, Yoh ; 吉岡, 和晃 ; 安藝, 翔 ; 多久和, 典子 ; 多久和, 陽
概要:
金沢大学医薬保健研究域医学系<br />Pinocytosis is an important fundamental cellular process that is used by the cell to transport fluid
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and solutes. Phosphoinositide 3-kinases (PI3Ks) regulate a diverse array of dynamic membrane events. However, it is not well-understood which PI3K isoforms are involved in specific mechanisms of pinocytosis. We performed knockdown studies of endogenous PI3K isoforms and clathrin heavy chain (CHC) mediated by small interfering RNA (siRNA). The results demonstrated that the class II PI3K PI3K-C2α and PI3K-C2β, but not the class I or III PI3K, were required for pinocytosis, based on an evaluation of fluorescein-5-isothiocyanate (FITC)–dextran uptake in endothelial cells. Pinocytosis was partially dependent on both clathrin and dynamin, and both PI3K-C2α and PI3K-C2β were required for clathrin-mediated—but not clathrin-non-mediated—FITC-dextran uptake at the step leading up to its delivery to early endosomes. Both PI3K-C2α and PI3K-C2β were co-localized with clathrin-coated pits and vesicles. However, PI3K-C2β, but not PI3K-C2α, was highly co-localized with actin filament-associated clathrin-coated structures and required for actin filament formation at the clathrin-coated structures. These results indicate that PI3K-C2α and PI3K-C2β play differential, indispensable roles in clathrin-mediated pinocytosis. © 2018, The Physiological Society of Japan and Springer Japan KK, part of Springer Nature.<br />Embargo Period 12 months
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Sarker, Md Azadul Kabir ; Aki, Sho ; Yoshioka, Kazuaki ; Kuno, Kouji ; Okamoto, Yasuo ; Ishimaru, Kazuhiro ; Takuwa, Noriko ; Takuwa, Yoh ; 安藝, 翔 ; 吉岡, 和晃 ; 多久和, 典子 ; 多久和, 陽
概要:
金沢大学医薬保健研究域医学系<br />Class II phosphoinositide 3-kinases (PI3Ks), PI3K-C2α and PI3K-C2β, are highly homologous and distin
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ct from class I and class III PI3Ks in catalytic products and domain structures. In contrast to class I and class III PI3Ks, physiological roles of PI3K-C2α and PI3K-C2β are not fully understood. Because we previously demonstrated that PI3K-C2α is involved in vascular smooth muscle contraction, we studied the phenotypes of smooth muscle-specific knockout (KO) mice of PI3K-C2α and PI3K-C2β. The pup numbers born from single PI3K-C2α-KO and single PI3K-C2β-KO mothers were similar to those of control mothers, but those from double KO (DKO) mothers were smaller compared with control mice. However, the number of intrauterine fetuses in pregnant DKO mothers was similar to that in control mice. Both spontaneous and oxytocin-induced contraction of isolated uterine smooth muscle (USM) strips was diminished in DKO mice but not in either of the single KO mice, compared with control mice. Furthermore, contraction of USM of DKO mice was less sensitive to a Rho kinase inhibitor. Mechanistically, the extent of oxytocin-induced myosin light chain phosphorylation was greatly reduced in USM from DKO mice compared with control mice. The oxytocin-induced rise in the intracellular Ca2+ concentration in USM was similar in DKO and control mice. However, Rho activation in the intracellular compartment was substantially attenuated in DKO mice compared with control mice, as evaluated by fluorescence resonance energy transfer imaging technique. These data indicate that both PI3K-C2α and PI3K-C2β are required for normal USM contraction and parturition mainly through their involvement in Rho activation.<br />Embargo Period 12 months
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多久和, 典子
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金沢大学大学院医学系研究科血管分子生理学<br />総説
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多久和, 典子 ; Takuwa, Noriko
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金沢大学医学系研究科<br />スフィンゴシン-1-リン酸(S1P)は血漿、血清中に存在する脂質メディエーターであり、複数のG蛋白共役型受容体サブタイプを介して多彩な生物活性を発揮する。S1P産生酵素SPHKは、系統発生上酵母の段階から同定
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されており、その欠損により代謝・成長・熱ショック反応などの異常がおこることが報告されている。ほ乳動物における主要なS1P産生酵素とされるSPHK1のノックアウトマウスは野生型と変わらない表現型を示すことから、ほ乳動物においてはSPHK1は必須ではないと考えられている。一方、S1PならびにSPHK1の各種病態における役割については十分解明されていない。一方、S1Pは活性化血小板から大量に放出されることから、血小板活性化を伴うがん、心血管リモデリングなどの病態における関与が示唆されている。なかでも興味深いのは、虚血性心疾患の患者において血清中のS1P濃度が上昇しており、しかも重症度と相関するという最近の報告である。本研究において、S1Pの病態生理学的意義を明らかにする目的で、SPHK1のトランスジェニック(Tg)マウスを作出し、発現レベルの異なる複数の系統を得た。高発現の系統では心、腎、骨格筋、皮膚などの抽出液中、野生型と比し3〜30倍のSPHK活性を検出した。いずれの系統も雌雄ともに同腹野生型と比較して、成長、生殖、育仔、悪性腫瘍の自然発症に顕著な異常をみとめず、また生存期間も現時点において著変は観察されない。しかしながら、高発現系統において成長後、心筋線維化が出現し、加齢に伴い増悪することを見出した。これはANP,βMHCなどの遺伝子高発現、低分子量G蛋白Rho, Racの活性上昇を伴っていた。本研究の結果は、心筋リモデリングにおいてS1Pが重要な(悪い)役割を演じていることを示唆する。(論文投稿準備中)。<br />The sphingosine-1-phosphate (S1P) signaling system plays crucial roles in diverse biological phenomena, which include embryonic vascular maturation and lymphocyte trafficking. It is also implicated in development of certain diseases such as cancer. In an attempt to elucidate pathophysiological role, if any, of the S1P signaling system, we have generated transgenic (TG) mice that overexpress SPHK1 in diverse tissues, with up to several ten fold increases in the enzymatic activity. Although TG x TG matings yielded a slightly reduced litter size, the TG mice grew normally without any obvious abnormality. Notably, TG mice with a high but not a low level of SPHK1 expression in the heart showed age-dependent, progressive cardiac fibrosis. Transgenic heart tissues showed embryonic gene upregulation, elevated Rac1 and RhoA activities and increased oxidative stress. Treatment of TG mice with an HMG-CoA reductase inhibitor or an antioxidant N-2-mercaptopropyonylglycine, but not an angiotensin II type 1 receptor blocker, resulted in alleviation of cardiac fibrosis. TG mice also developed modest renal glomerular dysfunction with age. Unexpectedly, the TG mice did not show a propensity for spontaneous malignancy or reduced lifespan as compared to the wild type littermates. These results provide evidence for a pathophysiological role of SPHK1 in cardiac remodeling and glomerular injury.<br />研究課題/領域番号:16590221, 研究期間(年度):2004 – 2005<br />出典：「スフィンゴシン-1-リン酸情報伝達系の生理学・病態生理学:個体レベルにおける解析」研究成果報告書 課題番号16590221（KAKEN：科学研究費助成事業データベース（国立情報学研究所））（https://kaken.nii.ac.jp/ja/report/KAKENHI-PROJECT-16590221/165902212005kenkyu_seika_hokoku_gaiyo/)を加工して作成
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