Advance

HARA Yuta

    Department of Pharmacy　Lecturer
Last Updated :2024/04/25

Researcher Information

Research funding number

  • 20803779

J-Global ID

Research Interests

  • 神経化学   免疫学   ケモカイン   癌   神経精神疾患   Pharmacology   

Research Areas

  • Life sciences / Immunology
  • Life sciences / Pharmacology

Academic & Professional Experience

  • 2022/04 - Today  近畿大学 薬学部講師
  • 2017/04 - 2022/03  Kindai UniversityFaculty of Pharmacy助教
  • 2013/04 - 2016/03  日本学術振興会特別研究員DC1

Education

  • 2013/04 - 2017/03  大阪大学大学院  薬学研究科  創成薬学専攻 博士後期課程
  • 2011/04 - 2013/03  大阪大学大学院  薬学研究科  創成薬学専攻 博士前期課程
  • 2007/04 - 2011/03  Osaka University  School of Pharmaceutical Sciences  薬科学科

Published Papers

  • Yuta Hara; Tatsuma Honzawa; Moeka Kitagawa; Ritsuki Sano; Kazuhiko Matsuo; Takashi Nakayama
    Journal of Pharmacological Sciences Elsevier BV 153 (3) 89 - 93 1347-8613 2023/11 
    Increasing evidence indicates that immune abnormalities are associated with the pathogenesis of depression. CCR4 is a chemokine receptor that regulates regulatory T cell (Treg) and Th17 cell migration. Here, using a lipopolysaccharide (LPS)-induced depression mouse model, we demonstrated that CCR4 deficiency exacerbated depressive-like behavior. Tregs and M2 macrophages, but not Th17 cells, were decreased in the brain of CCR4-deficient mice. Consistently, treatment with a CCR4 inhibitor reduced Tregs and M2 macrophages in the brain and exacerbated depressive-like behavior. Thus, CCR4 may contribute to the reduction of depressive symptoms by promoting Treg recruitment to the brain and subsequent M2 macrophage polarization.
  • Masako Sato; Kazuhiko Matsuo; Yoko Susami; Ayaka Yamashita; Haruko Hayasaka; Yuta Hara; Keiji Nishiwaki; Naoki Oiso; Akira Kawada; Atsushi Otsuka; Takashi Nakayama
    International Immunology Oxford University Press (OUP) 35 (9) 437 - 446 2023/06 
    CCR4 is a major trafficking receptor for Th2 cells and Th17 cells and is considered as a potential therapeutic target for atopic dermatitis (AD). The CCR4 ligands CCL17 and CCL22 have been reported to be upregulated in the skin lesions of AD patients. Of note, Thymic stromal lymphopoietin (TSLP), a master regulator of the Th2 immune response, promotes the expression of CCL17 and CCL22 in AD skin lesions. Here, we investigated the role of CCR4 in an AD mouse model induced by MC903, a TSLP inducer. Topical application of MC903 to ear skin increased the expression of not only TSLP but also CCL17, CCL22, the Th2 cytokine IL-4, and the Th17 cytokine IL-17A. Consistently, MC903 induced AD-like skin lesions as shown by increased epidermal thickness; increased infiltration of eosinophils, mast cells, type 2 innate lymphoid cells, Th2 cells, and Th17 cells; and elevated serum levels of total IgE. We also found increased expansion of Th2 cells and Th17 cells in the regional lymph nodes (LNs) of AD mice. Compound 22, a CCR4 inhibitor, ameliorated AD-like skin lesions with reduction of Th2 cells and Th17 cells in the skin lesions and regional LNs. We further confirmed that compound 22 diminished the expansion of Th2 cells and Th17 cells in the coculture of CD11c + dendritic cells and CD4 + T cells derived from the regional LNs of AD mice. Collectively, CCR4 antagonists may exhibit anti-allergic effects by inhibiting both the recruitment and expansion of Th2 cells and Th17 cells in AD.
  • Akitaka Yamasaki; Rikuto Miyake; Yuta Hara; Hideki Okuno; Takuya Imaida; Kouki Okita; Shogo Okazaki; Yasutoshi Akiyama; Kenji Hirotani; Yuichi Endo; Kazue Masuko; Takashi Masuko; Yoshihisa Tomioka
    Cancer Medicine Wiley 2045-7634 2023/02 
    Colorectal cancer (CRC) is the most common malignancy in the world, and novel molecular targeted therapies for CRC have been vigorously pursued. We searched for novel combination therapies based on the expression patterns of membrane proteins in CRC cell lines. A positive correlation was observed between the expression of human pidermal growth factor receptor (HER) 3 and mesenchymal-to-epithelial transition factor (MET) on the cell surface of CRC cell lines. The brief stimulation of HER3/MET-high SW1116 CRC cells with both neuregulin-1 (NRG1) and hepatocyte growth factor enhanced ERK phosphorylation and cell proliferation more than each stimulation alone. In addition, a prolonged NRG1 stimulation resulted in the tyrosine phosphorylation of MET. In this context, the Forkhead Box protein M1 (FOXM1)-regulated tyrosine phosphorylation of MET by NRG1 was demonstrated, suggesting the existence of a signaling pathway mediated by FOXM1 upon the NRG1 stimulation. Since the co-expression of HER3 and MET was also demonstrated in in vivo CRC tissues by immunohistochemistry, we investigated whether the co-inhibition of HER3 and MET could be an effective therapy for CRC. We established HER3-and/or MET-KO SW1116 cell lines, and HER3/MET-double KO resulted in the inhibition of in vitro cell proliferation and in vivo tumor growth in nude mice by SW1116 cells. Furthermore, the combination of patritumab, an anti-HER3 fully human mAb, and PHA665752, a MET inhibitor, markedly inhibited in vitro cell proliferation, 3D-colony formation, and in vivo tumor growth in nude mice by SW1116 cells. The dual targeting of HER3/MET has potential as CRC therapy.
  • Tatsuma Honzawa; Kazuhiko Matsuo; Shunya Hosokawa; Mayu Kamimura; Yuichiro Kaibori; Yuta Hara; Daisuke Nagakubo; Naoki Oiso; Akira Kawada; Atsushi Otsuka; Osamu Yoshie; Takashi Nakayama
    International immunology 34 (12) 635 - 642 2022/08 
    Th17 cells express CCR4 and secrete cytokines such as IL-17A and GM-CSF, while dendritic cells (DCs) produce CCL22, a CCR4 ligand, upon stimulation with GM-CSF. Th17 cells are known to play a critical role in the pathogenesis of rheumatoid arthritis (RA). CCL22 has also been shown to be upregulated in the synovial tissues of RA patients. Here, we investigated the role of CCR4 in collagen-induced arthritis (CIA), a mouse model of RA. DBA/1J mice efficiently developed CIA as shown by erythema, paw swelling, joint rigidity, and joint destruction. Th17 cells were increased in the arthritic joints and regional lymph nodes (LNs) of CIA mice. A fraction of Th17 cells were also shown to produce GM-CSF. On the other hand, we observed no significant increases of Th2 cells or Treg cells, the T cell subsets also known to express CCR4, in these tissues. We further observed clusters of CCR4-expressing memory Th17 cells and CCL22-producing DCs in the regional LNs of CIA mice, supporting the role of the CCR4-CCL22 axis in the expansion of Th17 cells in the regional LNs. Compound 22, a CCR4 inhibitor, ameliorated the disease severity with reduction of Th17 cells in the arthritic joints and regional LNs and Th17-DC clusters in the regional LNs. We further confirmed that CCR4-deficient mice in the C57BL/6J background were highly resistant to CIA induction compared with wild-type mice. Collectively, CCR4 contributes to the pathogenesis of CIA and may thus represent a new therapeutic target for RA.
  • Kosuke Kitahata; Kazuhiko Matsuo; Masako Sato; Yoko Susami; Yuta Hara; Toshio Morikawa; Naoki Oiso; Akira Kawada; Atsushi Otsuka; Takashi Nakayama
    Experimental dermatology 31 (8) 1234 - 1242 2022/04 
    Atopic dermatitis (AD) is the most common inflammatory skin disease, which is characterized by excessive Th2 immune responses. In AD patients, the expression of the chemokines CCL17 and CCL22 is increased in skin lesions, leading to the infiltration of Th2 cells. In addition, typical pro-inflammatory cytokines, including TNF-α, IL-1β and IL-6, have also been shown to be associated with the pathogenesis of AD. Recently, DDH-1, an ascorbic acid derivative, has been synthesized and demonstrated to have a more stabilized structure and better skin penetrability. Furthermore, DDH-1 has been shown to suppress pro-inflammatory cytokine expression in vitro and in vivo. Therefore, using an AD mouse model, we evaluated the effect of DDH-1 to reduce allergic skin inflammation. We found that cutaneous administration of DDH-1 significantly reduced the expression levels of TNF-α, IL-1β and IL-6 in the skin lesions of AD-like mice. Additionally, DDH-1 administration also significantly reduced the expression levels of CCL17 and CCL22, resulting in decreased skin infiltration of Th2 cells. Consequently, DDH-1 reduced ear and epidermal thickness, the serum IgE levels and the number of infiltrating inflammatory cells and mast cells into the AD-like skin lesions. Combination treatment with DDH-1 and corticosteroid more efficiently improved the skin lesions compared with corticosteroid alone. Collectively, our results suggest that DDH-1 has an anti-allergic effect in an AD mouse model by reducing not only the pro-inflammatory cytokine expression but also the Th2-associated chemokine expression. Thus, DDH-1 may be beneficial for AD treatment and prevention as a monotherapy or in combination with corticosteroids.
  • Kazuhiko Matsuo; Kosuke Kitahata; Yuichiro Kaibori; Yuka Arima; Arisa Iwama; Mana Ito; Yuta Hara; Daisuke Nagakubo; Ying-Shu Quan; Fumio Kamiyama; Naoki Oiso; Akira Kawada; Osamu Yoshie; Takashi Nakayama
    The Journal of investigative dermatology 141 (8) 1985 - 1994 2021/08 
    Psoriasis is a chronic skin disease associated with T helper (Th)17-mediated inflammation. Because CCR4 is a major chemokine receptor expressed on Th17 cells, we investigated the role of CCR4 in a modified imiquimod-induced psoriasis model that showed enhanced skin infiltration of Th17 cells. CCR4-deficient mice had less severe skin disease than wild-type mice. Th17 cells were decreased in the skin lesions and regional lymph nodes of CCR4-deficient mice. In the regional lymph nodes of wild-type mice, CD44+ memory Th17 cells expressing CCR4 were found to be clustered with dendritic cells expressing CCL22, a ligand for CCR4. Such dendritic cell‒Th17 cell clusters were significantly decreased in CCR4-deficient mice. Similar results were obtained using the IL-23‒induced psoriasis model. In vitro, compound 22, a CCR4 antagonist, significantly reduced the expansion of Th17 cells in the coculture of CD11c+ dendritic cells and CD4+ T cells separately prepared from the regional lymph nodes of wild-type mice with psoriasis. In vivo, compound 22 ameliorated the psoriasis-like skin disease in wild-type mice with significant decreases of Th17 cells in the regional lymph nodes and skin lesions. Collectively, CCR4 is likely to play a role in the pathogenesis of psoriasis through the expansion of Th17 cells.
  • Kazuhiko Matsuo; Osamu Yoshie; Kosuke Kitahata; Momo Kamei; Yuta Hara; Takashi Nakayama
    Cancers 13 (10) 2021/05 
    Cancer immunotherapy aims to treat cancer by enhancing cancer-specific host immune responses. Recently, cancer immunotherapy has been attracting much attention because of the successful clinical application of immune checkpoint inhibitors targeting the CTLA-4 and PD-1/PD-L1 pathways. However, although highly effective in some patients, immune checkpoint inhibitors are beneficial only in a limited fraction of patients, possibly because of the lack of enough cancer-specific immune cells, especially CD8+ cytotoxic T-lymphocytes (CTLs), in the host. On the other hand, studies on cancer vaccines, especially DC-based ones, have made significant progress in recent years. In particular, the identification and characterization of cross-presenting DCs have greatly advanced the strategy for the development of effective DC-based vaccines. In this review, we first summarize the surface markers and functional properties of the five major DC subsets. We then describe new approaches to induce antigen-specific CTLs by targeted delivery of antigens to cross-presenting DCs. In this context, the chemokine receptor XCR1 and its ligand XCL1, being selectively expressed by cross-presenting DCs and mainly produced by activated CD8+ T cells, respectively, provide highly promising molecular tools for this purpose. In the near future, CTL-inducing DC-based cancer vaccines may provide a new breakthrough in cancer immunotherapy alone or in combination with immune checkpoint inhibitors.
  • Kouki Okita; Yuta Hara; Hiroshi Okura; Hidemi Hayashi; Yoko Sasaki; Sachiko Masuko; Eri Kitadai; Kazue Masuko; Soshi Yoshimoto; Natsumi Hayashi; Reiko Sugiura; Yuichi Endo; Shogo Okazaki; Sayaka Arai; Toshiaki Yoshioka; Toshiharu Matsumoto; Yasutaka Makino; Hiromitsu Komiyama; Kazuhiro Sakamoto; Takashi Masuko
    Cancer science 112 (2) 563 - 574 2021/02 
    Copy number alterations detected by comparative genomic hybridization (CGH) can lead to the identification of novel cancer-related genes. We analyzed chromosomal aberrations in a set of 100 human primary colorectal cancers (CRCs) using CGH and found a solute carrier (SLC) 7A1 gene, which encodes cationic amino acid transporter 1 (CAT1) with 14 putative transmembrane domains, in a chromosome region (13q12.3) with a high frequency of gene amplifications. SLC7A1/CAT1 is a transporter responsible for the uptake of cationic amino acids (arginine, lysine, and ornithine) essential for cellular growth. Microarray and PCR analyses have revealed that mRNA transcribed from CAT1 is overexpressed in more than 70% of human CRC samples, and RNA interference-mediated knockdown of CAT1 inhibited the cell growth of CRCs. Rats were immunized with rat hepatoma cells expressing CAT1 tagged with green fluorescent protein (GFP), and rat splenocytes were fused with mouse myeloma cells. Five rat monoclonal antibodies (mAbs) (CA1 ~ CA5) reacting with HEK293 cells expressing CAT1-GFP in a GFP expression-dependent manner were selected from established hybridoma clones. Novel anti-CAT1 mAbs selectively reacted with human CRC tumor tissues compared with adjacent normal tissues according to immuno-histochemical staining and bound strongly to numerous human cancer cell lines by flow cytometry. Anti-CAT1 mAbs exhibited internalization activity, antibody-dependent cellular cytotoxicity, and migration inhibition activity against CRC cell lines. Furthermore, CA2 inhibited the in vivo growth of human HT29 and SW-C4 CRC tumors in nude mice. This study suggested CAT1 to be a promising target for mAb therapy against CRCs.
  • Shinya Yamamoto; Kazuhiko Matsuo; Sho Sakai; Itsuki Mishima; Yuta Hara; Naoki Oiso; Akira Kawada; Osamu Yoshie; Takashi Nakayama
    International immunology 33 (1) 49 - 55 2021/01 
    Extracellular ATP is known to promote Th17 cell differentiation in the intestinal lamina propria by stimulating CD70+CD11clow dendritic cells (DCs) via P2X receptors (P2XRs). Recent studies have also shown that Th17 cells enhance antitumor immunity by directly promoting proliferation of cytotoxic T lymphocytes (CTLs). These finding led us to test a P2XR agonist, αβ-methylene ATP (αβ-ATP), as a mucosal vaccine adjuvant to promote CTL responses through Th17 induction. We demonstrated that (i) CD70+CD11clow DCs were present in the nasal lamina propria and expressed P2X1R, P2X2R and P2X4R; (ii) CD70+CD11clow DCs isolated from the nasal lamina propria enhanced Th17 cell differentiation of cocultured splenic CD4+ T cells upon stimulation with αβ-ATP; (iii) mice intranasally immunized with ovalbumin (OVA) and αβ-ATP had increased OVA-specific Th17 cells and CTLs in the nasal lamina propria and regional lymph nodes; (iv) mice intranasally immunized with OVA and αβ-ATP also had elevated resistance to E.G7-OVA tumor growth compared with those intranasally immunized with OVA alone; (v) suramin, a broad-range inhibitor of P2 receptors, suppressed the increases of OVA-specific Th17 cells and CTLs in mice intranasally immunized with OVA and αβ-ATP; and (vi) suramin also abrogated the enhanced antitumor immunity of mice intranasally immunized with OVA and αβ-ATP against E.G7-OVA. Collectively, αβ-ATP may be a promising mucosal adjuvant that promotes antigen-specific CTL responses via CD70+CD11clow DC-mediated Th17 induction.
  • Momo Kamei; Kazuhiko Matsuo; Haruka Imanishi; Yuta Hara; Ying-Shu Quen; Fumio Kamiyama; Naoki Oiso; Akira Kawada; Naoki Okada; Takashi Nakayama
    Journal of pharmacological sciences Elsevier BV 143 (3) 182 - 187 1347-8613 2020/07 [Refereed]
     
    Memory CD8+ cytotoxic T-lymphocytes (CTLs) play a key role in protective immunity against infection and cancer. However, the induction of memory CTLs with currently available vaccines remains difficult. The chemokine receptor XCR1 is predominantly expressed on CD103+ cross-presenting dendritic cells (DCs). Recently, we have demonstrated that a high activity form of murine lymphotactin/XCL1 (mXCL1-V21C/A59C), a ligand of XCR1, can induce antigen-specific memory CTLs by increasing the accumulation of CD103+ DCs in the vaccination site and the regional lymph nodes. Here, we combined a hydrophilic gel patch as a transcutaneous delivery device and mXCL1-V21C/A59C as an adjuvant to further enhance memory CTL responses. The transcutaneous delivery of ovalbumin (OVA) and mXCL1-V21C/A59C by the hydrophilic gel patch increased CD103+ DCs in the vaccination site and the regional lymph nodes for a prolonged period of time compared with the intradermal injection of OVA and mXCL1-V21C/A59C. Furthermore, the hydrophilic gel patch containing OVA and mXCL1-V21C/A59C strongly induced OVA-specific memory CTLs and efficiently inhibited the growth of OVA-expressing tumors more than the intradermal injection of OVA and mXCL1-V21C/A59C. Collectively, this type of hydrophilic gel patch and a high activity form of XCL1 may provide a useful tool for the induction of memory CTL responses.
  • Yuta Hara; Yushi Minami; Soshi Yoshimoto; Natsumi Hayashi; Akitaka Yamasaki; Shiho Ueda; Kazue Masuko; Takashi Masuko
    Cancer medicine 9 (1) 302 - 312 2020/01 [Refereed]
     
    KRAS mutations are detected in numerous human cancers, but there are few effective drugs for KRAS-mutated cancers. Transporters for amino acids and glucose are highly expressed on cancer cells, possibly to maintain rapid cell growth and metabolism. Alanine-serine-cysteine transporter 2 (ASCT2) is a primary transporter for glutamine in cancer cells. In this study, we developed a novel monoclonal antibody (mAb) recognizing the extracellular domain of human ASCT2, and investigated whether ASCT2 can be a therapeutic target for KRAS-mutated cancers. Rats were immunized with RH7777 rat hepatoma cells expressing human ASCT2 fused to green fluorescent protein (GFP). Splenocytes from the immunized rats were fused with P3X63Ag8.653 mouse myeloma cells, and selected and cloned hybridoma cells secreting Ab3-8 mAb were established. This mAb reacted with RH7777 transfectants expressing ASCT2-GFP proteins in a GFP intensity-dependent manner. Ab3-8 reacted with various human cancer cells, but not with non-cancer breast epithelial cells or ASCT2-knocked out HEK293 and SW1116 cells. In SW1116 and HCT116 human colon cancer cells with KRAS mutations, treatment with Ab3-8 reduced intracellular glutamine transport, phosphorylation of AKT and ERK, and inhibited in vivo tumor growth of these cells in athymic mice. Inhibition of in vivo tumor growth by Ab3-8 was not observed in HT29 colon and HeLa uterus cancer cells with wild-type KRAS. These results suggest that ASCT2 is an excellent therapeutic target for KRAS-mutated cancers.
  • Shiho Ueda; Hidemi Hayashi; Takako Miyamoto; Shinya Abe; Kana Hirai; Kanji Matsukura; Hideki Yagi; Yuta Hara; Kinji Yoshida; Shogo Okazaki; Masakazu Tamura; Yuki Abe; Toshinori Agatsuma; Shin-Ichiro Niwa; Kazue Masuko; Takashi Masuko
    Cancer science 110 (2) 674 - 685 1347-9032 2019/02 [Refereed]
     
    L-Type amino acid transporter 1 (LAT1) disulfide linked to CD98 heavy chain (hc) is highly expressed in most cancer cells, but weakly expressed in normal cells. In the present study, we developed novel anti-LAT1 mAbs and showed internalization activity, inhibitory effects of amino acid uptake and cell growth and antibody-dependent cellular cytotoxicity, as well as in vivo antitumor effects in athymic mice. Furthermore, we examined the reactivity of mAbs with LAT1 of Macaca fascicularis to evaluate possible side-effects of antihuman LAT1 mAbs in clinical trials. Antihuman LAT1 mAbs reacted with ACHN human and MK.P3 macaca kidney-derived cells, and this reactivity was significantly decreased by siRNAs against LAT1. Macaca LAT1 cDNA was cloned from MK.P3, and only two amino acid differences between human and macaca LAT1 were seen. RH7777 rat hepatoma and HEK293 human embryonic kidney cells expressing macaca LAT1 were established as stable transfectants, and antihuman LAT1 mAbs were equivalently reactive against transfectants expressing human or macaca LAT1. Dual (high and low) avidity modes were detected in transfectants expressing macaca LAT1, MK.P3, ACHN and HCT116 human colon cancer cells, and KA values were increased by anti-CD98hc mAb, suggesting anti-LAT1 mAbs detect an epitope on LAT1-CD98hc complexes on the cell surface. Based on these results, LAT1 may be a promising anticancer target and Macaca fascicularis can be used in preclinical studies with antihuman LAT1 mAbs.
  • Haruki Kawase; Yukio Ago; Megumi Naito; Momoko Higuchi; Yuta Hara; Shigeru Hasebe; Shinji Tsukada; Atsushi Kasai; Takanobu Nakazawa; Tadashi Mishina; Hiroyuki Kouji; Kazuhiro Takuma; Hitoshi Hashimoto
    Pharmacology, biochemistry, and behavior 176 1 - 5 0091-3057 2019/01 [Refereed]
     
    Growing evidence suggests pivotal roles for epigenetic mechanisms in both animal models of and individuals with autism spectrum disorders (ASD). Neuron-restrictive silencer factor (NRSF) binds to neuron-restrictive silencing elements in neuronal genes and recruits co-repressors, such as mSin3, to epigenetically inhibit neuronal gene expression. Because dysregulation of NRSF is related to ASD, here we examined the effects of mS-11, a chemically optimized mimetic of the mSin3-binding helix in NRSF, on the behavioral and morphological abnormalities found in a mouse model of valproic acid (VPA)-induced ASD. Chronic treatment with mS-11 improved prenatal VPA-induced deficits in social interaction. Additionally, we found that NRSF mRNA expression was greater in the somatosensory cortex of VPA-exposed mice than of controls. Agreeing with these behavioral findings, mice that were prenatally exposed to VPA showed lower dendritic spine density in the somatosensory cortex, which was reversed by chronic treatment with mS-11. These findings suggest that mS-11 has the potential for improving ASD-related symptoms through inhibition of mSin3-NRSF binding.
  • Kazuhiko Matsuo; Shota Hatanaka; Yuta Kimura; Yuta Hara; Keiji Nishiwaki; Ying-Shu Quan; Fumio Kamiyama; Naoki Oiso; Akira Kawada; Kenji Kabashima; Takashi Nakayama
    Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 109 1437 - 1444 0753-3322 2019/01 [Refereed]
     
    CCR4 is a chemokine receptor highly expressed by Th2 cells, and regarded as a potential therapeutic target for atopic dermatitis (AD). CCL17 and CCL22 are the CCR4 ligands, and thymic stromal lymphopoietin (TSLP) is shown to promote the expression of CCL17 and CCL22 by dendritic cells. Here, by using dibutyl phthalate (DBP), a TSLP inducer, and a hydrogel patch as a transcutaneous delivery device for ovalbumin, we developed a novel murine AD model and investigated the effect of Compound 22, a CCR4 antagonist. We first found that the mRNA expression of TSLP together with CCL17 and CCL22 was increased in the skins treated with DBP. Furthermore, the topical application of ovalbumin and DBP efficiently and rapidly induced AD-like skin lesions in BALB/c mice, which were characterized by ear swelling accompanied by infiltration of eosinophils, mast cells, and CCR4-expressing Th2 cells in the skin lesions, and elevated total IgE levels in the sera. Using this AD model, we demonstrated that cutaneous administration of Compound 22 inhibited Th2 cell infiltration and ameliorated the AD-like skin lesions. These results suggest that our AD model could be useful for studying new therapeutic strategies. Collectively, CCR4 antagonists may be a promising approach for treating AD.
  • Yuta Hara
    Yakugaku zasshi : Journal of the Pharmaceutical Society of Japan 139 (11) 1391 - 1396 0031-6903 2019 [Refereed]
     
    Over the last decade there has been an increase in the prevalence of autism spectrum disorder (ASD); however, its pathogenic mechanisms remain unclear. To date, no effective drug has been developed to treat the core symptoms of ASD, especially social interaction deficits. Previous studies have mainly focused on the glutamatergic, GABAergic, and serotonergic signaling pathways; however, a growing number of studies have reported abnormalities in the dopaminergic pathway, such as mutations and functional alterations of dopamine-related molecules, in ASD patients. Furthermore, atypical antipsychotic drugs risperidone and aripiprazole are prescribed for the treatment of non-core symptoms, such as irritability, in patients with ASD. These observations suggest that the dopaminergic pathway is involved in the pathogenesis of ASD. Previously, we have established a mouse model of ASD based on clinical research, which shows that exposure to valproic acid, an antiepileptic drug, during pregnancy causes an increase in the risk of developing ASD in children. This review summarizes our recent studies, which have assessed alterations in the prefrontal dopaminergic pathway. In addition, we discuss the effects of treatment with attention deficit/hyperactivity disorder drugs and atypical antipsychotic drugs, which activate the prefrontal dopaminergic pathway, on ASD-like behavioral abnormalities in the valproic acid exposure mouse model of ASD.
  • Kosuke Kitahata; Kazuhiko Matsuo; Yuta Hara; Takanori Naganuma; Naoki Oiso; Akira Kawada; Takashi Nakayama
    Journal of pharmacological sciences 138 (4) 284 - 288 1347-8613 2018/12 [Refereed]
     
    Psoriasis is a chronic inflammatory skin disease in which inflammatory cytokines play a major role in its pathogenesis. Because DDH-1, a novel amphipathic ascorbic acid derivative, has been recently shown to reduce inflammatory cytokine expression in human keratinocytes in vitro, we investigated its effect on imiquimod-induced psoriasis-like skin lesions in C57BL/6 mice. We first found that IL-1β and TNF-α mRNA expression was significantly decreased in the skin lesions treated with DDH-1. Furthermore, cutaneous administration of DDH-1 ameliorated psoriasis-like skin lesions. These results suggest that DDH-1 may be effective in the prevention and supplemental treatment of psoriasis.
  • Yuta Hara; Ryota Torii; Shiho Ueda; Erina Kurimoto; Eri Ueda; Hiroshi Okura; Yutaka Tatano; Hideki Yagi; Yoshiya Ohno; Toshiyuki Tanaka; Kazue Masuko; Takashi Masuko
    Cancer science 109 (10) 3171 - 3182 1347-9032 2018/10 [Refereed]
     
    Although cancer metastasis is associated with poor prognosis, the mechanisms of this event, especially via lymphatic vessels, remain unclear. Lymphatic vessel endothelial hyaluronan receptor 1 (LYVE-1) is expressed on lymphatic vessel endothelium and is considered to be a specific marker of lymphatic vessels, but it is unknown how LYVE-1 is involved in the growth and metastasis of cancer cells. We produced rat monoclonal antibodies (mAb) recognizing the extracellular domain of mouse LYVE-1, and investigated the roles of LYVE-1 in tumor formation and metastasis. The mAb 38M and 64R were selected from hybridoma clones created by cell fusion between spleen cells of rats immunized with RH7777 rat hepatoma cells expressing green fluorescent protein (GFP)-fused mouse LYVE-1 proteins and mouse myeloma cells. Two mAb reacted with RH7777 and HEK293F human embryonic kidney cells expressing GFP-fused mouse LYVE-1 proteins in a GFP expression-dependent manner, and each recognized a distinct epitope. On immunohistology, the 38M mAb specifically stained lymphatic vessels in several mouse tissues. In the wound healing assay, the 64R mAb inhibited cell migration of HEK293F cells expressing LYVE-1 and mouse lymphatic endothelial cells (LEC), as well as tube formation by LEC. Furthermore, this mAb inhibited primary tumor formation and metastasis to lymph nodes in metastatic MDA-MB-231 xenograft models. This shows that LYVE-1 is involved in primary tumor formation and metastasis, and it may be a promising molecular target for cancer therapy.
  • Imai Kazuki; Ueda Shiho; Hara Yuta; Ishiwata Toshiyuki; Masuko Takashi
    CANCER SCIENCE 109 1062  1349-7006 2018/01 [Refereed]
  • Kazuhiko Matsuo; Kosuke Kitahata; Fumika Kawabata; Momo Kamei; Yuta Hara; Shiki Takamura; Naoki Oiso; Akira Kawada; Osamu Yoshie; Takashi Nakayama
    Frontiers in immunology 9 2775 - 2775 2018 [Refereed]
     
    The chemokine receptor XCR1 is known to be selectively expressed by cross-presenting dendritic cells (DCs), while its ligand XCL1/lymphotactin is mainly produced by activated CD8+ T cells and natural killer cells. Recent studies have shown that XCL1-antigen fusion proteins efficiently induce CD8+ T cell responses by preferentially delivering antigens to XCR1+ DCs. However, XCL1 per se was found to be a poor adjuvant for induction of CD8+ T cell responses. XCL1 is unique because of its lack of one of the two disulfide bonds commonly conserved in all other chemokines and thus has an unstable structure with a relatively weak chemokine activity. In the present study, we generated a variant form of murine XCL1 termed mXCL1-V21C/A59C that contained a second disulfide bond to stabilize its chemokine structure. We confirmed that mXCL1-V21C/A59C had much more potent chemotactic and calcium mobilization activities than the wild type XCL1 (mXCL1-WT). Intradermal injection of mXCL1-V21C/A59C, but not that of mXCL1-WT, significantly increased the accumulation of XCR1+CD103+ DCs in the injection site, and most of the accumulated XCR1+CD103+ DCs were found to take up co-injected ovalbumin (OVA). Furthermore, recruited XCR1+CD103+ DCs efficiently migrated to the draining lymph nodes and stayed for a prolonged period of time. Consequently, mXCL1-V21C/A59C strongly induced OVA-specific CD8+ T cells. The combination of OVA and mXCL1-V21C/A59C well protected mice from E.G7-OVA tumor growth in both prophylactic and therapeutic protocols. Finally, memory CTL responses were efficiently induced in mice immunized with OVA and mXCL1-V21C/A59C. Although intradermal injection of OVA and polyinosinic-polycytidylic acid (poly(I:C)) as an adjuvant also induced CD8+ T cell responses to OVA, poly (I:C) poorly recruited XCR1+CD103+ DCs in the injection site and failed to induce significant memory CTL responses to OVA. Collectively, our findings demonstrate that a highly active form of XCL1 is a promising vaccine adjuvant for cross-presenting DCs to induce antigen-specific effector and memory CD8+ T cells.
  • Yuta Hara; Yukio Ago; Atsuki Taruta; Shigeru Hasebe; Haruki Kawase; Wataru Tanabe; Shinji Tsukada; Takanobu Nakazawa; Hitoshi Hashimoto; Toshio Matsuda; Kazuhiro Takuma
    Psychopharmacology SPRINGER 234 (21) 3217 - 3228 0033-3158 2017/11 [Refereed]
     
    RATIONALE: Rodents exposed prenatally to valproic acid (VPA) exhibit autism spectrum disorder (ASD)-like behavioral abnormalities. We recently found that prenatal VPA exposure causes hypofunction of the prefrontal dopaminergic system in mice. This suggests that the dopaminergic system may be a potential pharmacological target for treatment of behavioral abnormalities in ASD patients. OBJECTIVES: In the present study, we examined the effects of antipsychotic drugs, which affect the dopaminergic system, on the social interaction deficits, recognition memory impairment, and reduction in dendritic spine density in the VPA mouse model of ASD. RESULTS: Both acute and chronic administrations of the atypical antipsychotic drugs risperidone and aripiprazole increased prefrontal dopamine (DA) release, while the typical antipsychotic drug haloperidol did not. Chronic risperidone and aripiprazole, but not haloperidol, increased the expression of c-Fos in the prefrontal cortex, although they all increased c-Fos expression in the striatum. Chronic, but not acute, administrations of risperidone and aripiprazole improved the VPA-induced social interaction deficits and recognition memory impairment, as well as the reduction in dendritic spine density in the prefrontal cortex and hippocampus. In contrast, chronic administration of haloperidol did not ameliorate VPA-induced abnormalities in behaviors and dendritic spine density. CONCLUSIONS: These findings indicate that chronic risperidone and aripiprazole treatments improve VPA-induced abnormalities in behaviors and prefrontal dendritic spine density, which may be mediated by repeated elevation of extracellular DA in the prefrontal cortex. Our results also imply that loss of prefrontal dendritic spines may be involved in the abnormal behaviors in the VPA mouse model of ASD.
  • Yuta Hara; Yukio Ago; Momoko Higuchi; Shigeru Hasebe; Takanobu Nakazawa; Hitoshi Hashimoto; Toshio Matsuda; Kazuhiro Takuma
    Hormones and behavior ACADEMIC PRESS INC ELSEVIER SCIENCE 96 130 - 136 0018-506X 2017/11 [Refereed]
     
    Recent studies have reported that oxytocin ameliorates behavioral abnormalities in both animal models and individuals with autism spectrum disorders (ASD). However, the mechanisms underlying the ameliorating effects of oxytocin remain unclear. In this study, we examined the effects of intranasal oxytocin on impairments in social interaction and recognition memory in an ASD mouse model in which animals are prenatally exposed to valproic acid (VPA). We found that a single intranasal administration of oxytocin restored social interaction deficits for up to 2h in mice prenatally exposed to VPA, but there was no effect on recognition memory impairments. Additionally, administration of oxytocin across 2weeks improved prenatal VPA-induced social interaction deficits for at least 24h. In contrast, there were no effects on the time spent sniffing in control mice. Immunohistochemical analysis revealed that intranasal administration of oxytocin increased c-Fos expression in the paraventricular nuclei (PVN), prefrontal cortex, and somatosensory cortex, but not the hippocampal CA1 and CA3 regions of VPA-exposed mice, suggesting the former regions may underlie the effects of oxytocin. These findings suggest that oxytocin attenuates social interaction deficits through the activation of higher cortical areas and the PVN in an ASD mouse model.
  • Hiroshi Yamaguchi; Yuta Hara; Yukio Ago; Erika Takano; Shigeru Hasebe; Takanobu Nakazawa; Hitoshi Hashimoto; Toshio Matsuda; Kazuhiro Takuma
    Behavioural brain research ELSEVIER SCIENCE BV 333 67 - 73 0166-4328 2017/08 [Refereed]
     
    We recently demonstrated that prenatal exposure to valproic acid (VPA) at embryonic day 12.5 causes autism spectrum disorder (ASD)-like phenotypes such as hypolocomotion, anxiety-like behavior, social deficits and cognitive impairment in mice and that it decreases dendritic spine density in the hippocampal CA1 region. Previous studies show that some abnormal behaviors are improved by environmental enrichment in ASD rodent models, but it is not known whether environmental enrichment improves cognitive impairment. In the present study, we examined the effects of early environmental enrichment on behavioral abnormalities and neuromorphological changes in prenatal VPA-treated mice. We also examined the role of dendritic spine formation and synaptic protein expression in the hippocampus. Mice were housed for 4 weeks from 4 weeks of age under either a standard or enriched environment. Enriched housing was found to increase hippocampal brain-derived neurotrophic factor mRNA levels in both control and VPA-exposed mice. Furthermore, in VPA-treated mice, the environmental enrichment improved anxiety-like behavior, social deficits and cognitive impairment, but not hypolocomotion. Prenatal VPA treatment caused loss of dendritic spines in the hippocampal CA1 region and decreases in mRNA levels of postsynaptic density protein-95 and SH3 and multiple ankyrin repeat domains 2 in the hippocampus. These hippocampal changes were improved by the enriched housing. These findings suggest that the environmental enrichment improved most ASD-like behaviors including cognitive impairment in the VPA-treated mice by enhancing dendritic spine function.
  • Yuta Hara; Yukio Ago; Erika Takano; Shigeru Hasebe; Takanobu Nakazawa; Hitoshi Hashimoto; Toshio Matsuda; Kazuhiro Takuma
    Molecular autism BIOMED CENTRAL LTD 8 33 - 33 2040-2392 2017 [Refereed]
     
    BACKGROUND: MicroRNAs, small non-coding RNAs, are highly expressed in the mammalian brain, and the dysregulation of microRNA levels may be involved in neurodevelopmental disorders such as autism spectrum disorder (ASD). In the present study, we examined whether prenatal valproic acid (VPA) exposure affects levels of microRNAs, especially the brain specific and enriched microRNAs, in the mouse embryonic brain. RESULTS: Prenatal exposure to VPA at E12.5 immediately increased miR-132 levels, but not miR-9 or miR-124 levels, in the male embryonic brain. Prenatal exposure to VPA at E12.5 also increased miR-132 levels in the female embryonic brain. We further found that the prenatal exposure to VPA at E12.5 increased mRNA levels of Arc, c-Fos and brain-derived neurotrophic factor in both male and female embryonic brains, prior to miR-132 expression. In contrast, prenatal exposure to VPA at E14.5 did not affect miR-132 levels in either male or female embryonic brain. The prenatal VPA exposure at E12.5 also decreased mRNA levels of methyl-CpG-binding protein 2 and Rho GTPase-activating protein p250GAP, both of which are molecular targets of miR-132. Furthermore, RNA sequence analysis revealed that prenatal VPA exposure caused changes in several microRNA levels other than miR-132 in the embryonic whole brain. CONCLUSIONS: These findings suggest that the alterations in neuronal activity-dependent microRNAs levels, including an increased level of miR-132, in the embryonic period, at least in part, underlie the ASD-like behaviors and cortical pathology produced by prenatal VPA exposure.
  • Yuta Hara; Yukio Ago; Atsuki Taruta; Keisuke Katashiba; Shigeru Hasebe; Erika Takano; Yusuke Onaka; Hitoshi Hashimoto; Toshio Matsuda; Kazuhiro Takuma
    Autism research : official journal of the International Society for Autism Research WILEY 9 (9) 926 - 39 1939-3792 2016/09 [Refereed]
     
    Rodents exposed prenatally to valproic acid (VPA) show autism-related behavioral abnormalities. We recently found that prenatal VPA exposure causes a reduction of dopaminergic activity in the prefrontal cortex of male, but not female, mice. This suggests that reduced prefrontal dopaminergic activity is associated with behavioral abnormalities in VPA-treated mice. In the present study, we examined whether the attention deficit/hyperactivity disorder drugs methylphenidate and atomoxetine (which increase dopamine release in the prefrontal cortex, but not striatum, in mice) could alleviate the behavioral abnormalities and changes in dendritic spine morphology induced by prenatal VPA exposure. We found that methylphenidate and atomoxetine increased prefrontal dopamine and noradrenaline release in VPA-treated mice. Acute treatment with methylphenidate or atomoxetine did not alleviate the social interaction deficits or recognition memory impairment in VPA-treated mice, while chronic treatment for 2 weeks did. Methylphenidate or atomoxetine for 2 weeks also improved the prenatal VPA-induced decrease in dendritic spine density in the prefrontal cortex. The effects of these drugs on behaviors and dendritic spine morphology were antagonized by concomitant treatment with the dopamine-D1 receptor antagonist SCH39166 or the dopamine-D2 receptor antagonist raclopride, but not by the α2 -adrenoceptor antagonist idazoxan. These findings suggest that chronic treatment with methylphenidate or atomoxetine improves abnormal behaviors and diminishes the reduction in spine density in VPA-treated mice via a prefrontal dopaminergic system-dependent mechanism. Autism Res 2016, 9: 926-939. © 2015 International Society for Autism Research, Wiley Periodicals, Inc.
  • Yuta Hara; Kazuhiro Takuma; Erika Takano; Keisuke Katashiba; Atsuki Taruta; Kosuke Higashino; Hitoshi Hashimoto; Yukio Ago; Toshio Matsuda
    Behavioural brain research ELSEVIER SCIENCE BV 289 39 - 47 0166-4328 2015/08 [Refereed]
     
    Previous studies suggest that dysfunction of neurotransmitter systems is associated with the pathology of autism in humans and the disease model rodents, but the precise mechanism is not known. Rodent offspring exposed prenatally to VPA shows autism-related behavioral abnormalities. The present study examined the effect of prenatal VPA exposure on brain monoamine neurotransmitter systems in male and female mice. The prenatal VPA exposure did not affect the levels of dopamine (DA), noradrenaline (NA), serotonin (5-HT) and their metabolites in the prefrontal cortex and striatum, while it significantly reduced methamphetamine (METH) (1.0 mg/kg)-induced hyperlocomotion in male offspring. In vivo microdialysis study demonstrated that prenatal VPA exposure attenuated METH-induced increases in extracellular DA levels in the prefrontal cortex, while it did not affect those in extracellular NA and 5-HT levels. Prenatal VPA exposure also decreased METH-induced c-Fos expression in the prefrontal cortex and the mRNA levels of DA D1 and D2 receptors in the prefrontal cortex. These effects of VPA were not observed in the striatum. In contrast to male offspring, prenatal VPA exposure did not affect METH-induced increases in locomotor activity and prefrontal DA levels and the D1 and D2 receptor mRNA levels in the prefrontal cortex in female offspring. These findings suggest that prenatal VPA exposure causes hypofunction of prefrontal DA system in a sex-dependent way.
  • Kazuhiro Takuma; Yuta Hara; Shunsuke Kataoka; Takuya Kawanai; Yuko Maeda; Ryo Watanabe; Erika Takano; Atsuko Hayata-Takano; Hitoshi Hashimoto; Yukio Ago; Toshio Matsuda
    Pharmacology, biochemistry, and behavior PERGAMON-ELSEVIER SCIENCE LTD 126 43 - 9 0091-3057 2014/11 [Refereed]
     
    We recently showed that prenatal exposure to valproic acid (VPA) in mice causes autism-like behavioral abnormalities, including social interaction deficits, anxiety-like behavior and spatial learning disability, in male offspring. In the present study, we examined the effect of prenatal VPA on cognitive function and whether the effect is improved by chronic treatment with VPA and sodium butyrate, histone deacetylase inhibitors. In addition, we examined whether the cognitive dysfunction is associated with hippocampal dendritic morphological changes. Mice given prenatal exposure to VPA exhibited novel object recognition deficits at 9 weeks of age, and that the impairment was blocked by chronic (5-week) treatment with VPA (30 mg/kg/d, i.p.) or sodium butyrate (1.2g/kg/d, i.p.) starting at 4 weeks of age. In agreement with the behavioral findings, the mice prenatally exposed to VPA showed a decrease in dendritic spine density in the hippocampal CA1 region, and the spine loss was attenuated by chronic treatment with sodium butyrate or VPA. Furthermore, acute treatment with sodium butyrate, but not VPA, significantly increased acetylation of histone H3 in the hippocampus at 30 min, suggesting the difference in the mechanism for the effects of chronic VPA and sodium butyrate. These findings suggest that prenatal VPA-induced cognitive dysfunction is associated with changes in hippocampal dendritic spine morphology.
  • Shunsuke Kataoka; Kazuhiro Takuma; Yuta Hara; Yuko Maeda; Yukio Ago; Toshio Matsuda
    The international journal of neuropsychopharmacology CAMBRIDGE UNIV PRESS 16 (1) 91 - 103 1461-1457 2013/02 [Refereed]
     
    Maternal use of valproic acid (VPA) during pregnancy has been implicated in the aetiology of autism spectrum disorders in children, and rodents prenatally exposed to VPA showed behavioural alterations similar to those observed in humans with autism. However, the exact mechanism for VPA-induced behavioural alterations is not known. To study this point, we examined the effects of prenatal exposure to VPA and valpromide, a VPA analog lacking histone deacetylase inhibition activity, on behaviours, cortical pathology and histone acetylation levels in mice. Mice exposed to VPA at embryonic day 12.5 (E12.5), but not at E9 and E14.5, displayed social interaction deficits, anxiety-like behaviour and memory deficits at age 4-8 wk. In contrast to male mice, the social interaction deficits (a decrease in sniffing behaviour) were not observed in female mice at age 8 wk. The exposure to VPA at E12.5 decreased the number of Nissl-positive cells in the middle and lower layers of the prefrontal cortex and in the lower layers of the somatosensory cortex at age 8 wk. Furthermore, VPA exposure caused a transient increase in acetylated histone levels in the embryonic brain, followed by an increase in apoptotic cell death in the neocortex and a decrease in cell proliferation in the ganglionic eminence. In contrast, prenatal exposure to valpromide at E12.5 did not affect the behavioural, biochemical and histological parameters. Furthermore, these findings suggest that VPA-induced histone hyperacetylation plays a key role in cortical pathology and abnormal autism-like behaviours in mice.
  • Yuta Hara; Yuko Maeda; Shunsuke Kataoka; Yukio Ago; Kazuhiro Takuma; Toshio Matsuda
    JOURNAL OF PHARMACOLOGICAL SCIENCES JAPANESE PHARMACOLOGICAL SOC 118 (4) 543 - 546 1347-8613 2012/04 [Refereed]
     
    We have recently shown that prenatal valproic acid (VPA) exposure causes autism spectrum disorders-like behavioral abnormalities and Nissl-positive cell loss in both prefrontal and somatosensory cortices in male mice. We have also found that VPA-induced social interaction deficits are observed in male but not female offspring. This study demonstrated that the exposure to VPA at embryonic day 12.5 significantly decreased Nissl-positive cell numbers in the prefrontal cortex, but not in the somatosensory cortex, in female offspring. These findings suggest that VPA-induced morphological abnormalities in the somatosensory cortex may be involved in the sex-dependent social interaction deficits.
  • Yuta Hara; Yuko Maeda; Shunsuke Kataoka; Yukio Ago; Kazuhiro Takuma; Toshio Matsuda
    Journal of pharmacological sciences JAPANESE PHARMACOLOGICAL SOC 118 (4) 543 - 6 1347-8613 2012 [Refereed]
     
    We have recently shown that prenatal valproic acid (VPA) exposure causes autism spectrum disorders-like behavioral abnormalities and Nissl-positive cell loss in both prefrontal and somatosensory cortices in male mice. We have also found that VPA-induced social interaction deficits are observed in male but not female offspring. This study demonstrated that the exposure to VPA at embryonic day 12.5 significantly decreased Nissl-positive cell numbers in the prefrontal cortex, but not in the somatosensory cortex, in female offspring. These findings suggest that VPA-induced morphological abnormalities in the somatosensory cortex may be involved in the sex-dependent social interaction deficits.

Conference Activities & Talks

  • ケモカイン受容体CCR4の関節リウマチ発症および増悪における役割
    本澤 龍茉; 松尾 一彦; 原 雄大; 中山 隆志
    日本薬学会第141年会  2021/03
  • 高活性型ケモカインXCL1の経皮ワクチンシステムへの応用によるメモリーCTL誘導効率の増強
    大月 真由子; 亀井 萌百; 松尾 一彦; 今西 遥香; 原 雄大; 権 英淑; 神山 文男; 岡田 直貴; 中山 隆志
    日本薬学会第141年会  2021/03
  • ケモカイン受容体CCR4の欠損が食物アレルギー様症状に与える影響
    長尾 遥佳; 松尾 一彦; 眞田 翔士; 原 雄大; 義江 修; 中山 隆志
    第138回日本薬理学会近畿部会  2020/11
  • 抗炎症作用を有する新規アスコルビン酸誘導体DDH-1のアトピー性皮膚炎病態における改善効果
    須佐美 陽子; 新間 凪; 西川 莉央; 松尾 一彦; 原 雄大; 中山 隆志
    第138回日本薬理学会近畿部会  2020/11
  • ケモカイン受容体CCR4は関節リウマチ病態の増悪に寄与する
    本澤 龍茉; 松尾 一彦; 原 雄大; 中山 隆志
    第138回日本薬理学会近畿部会  2020/11
  • 気管支喘息におけるケモカインCCL28の役割
    原 雄大; 松尾一彦; 義江 修; 中山隆志
    第138回日本薬理学会近畿部会  2020/11
  • ケモカイン受容体CCR4は制御性T細胞を介して食物アレルギーを抑制する
    長尾 遥佳; 松尾 一彦; 眞田 翔士; 原 雄大; 義江 修; 中山 隆志
    第70回日本薬学会関西支部大会  2020/10
  • 高活性型XCL1による局在制御システムを応用したがんワクチンアジュバントの創製
    亀井 萌百; 松尾 一彦; 原 雄大; 義江 修; 中山 隆志
    第36回日本DDS学会学術集会  2020/08
  • ケモカインCCL28は気管支喘息病態の発現に寄与する
    藤原 加奈; 原 雄大; 中山 葵; 松尾 一彦; 松田 将也; 奈邉 健; 義江 修; 中山 隆志
    日本薬学会第140年会  2020/03
  • バルプロ酸を曝露した動物モデルにおける機能奇形とその改善療法
    田熊 一敞; 原 雄大; 吾郷 由希夫; 橋本 均; 中澤 敬信; 松田 敏夫
    第29回日本臨床精神神経薬理学会  2019/10
  • 気管支喘息におけるCCL28 を介した免疫細胞の遊走制御機構の解析
    藤原 加奈; 原 雄大; 中山 葵; 松尾 一彦; 義江 修; 中山 隆志
    第69回日本薬学会関西支部総会・大会  2019/10
  • ドパミン神経系賦活化薬の慢性投与は自閉症モデルマウスの行動異常を改善する
    原 雄大
    第69回日本薬学会関西支部総会・大会  2019/10
  • HER3/MET ノックアウト(KO)大腸癌細胞の性状解析
    三宅 陸斗; 山崎 晶貴; 原 雄大; 大野 喜也; 益子 高
    第78回日本癌学会学術集会  2019/09
  • CAT1/ SLC7A1を標的とした抗癌抗体療法
    小掠 博; 益子 高; 原 雄大
    第78回日本癌学会学術集会  2019/09
  • 新規抗ASCT2モノクローナル抗体のヒト大腸癌と膵癌に対する抗 癌効果とinternalization活性
    吉本 蒼司; 原 雄大; 石渡 俊二; 益子 高
    第78回日本癌学会学術集会  2019/09
  • 癌遺伝子産物HER3とMETを標的とした革新的ヒト大腸癌治療に向けた研究  [Not invited]
    山崎 晶貴; 原 雄大; 三宅 陸斗; 益子 高
    日本薬学会第139年会  2019/03
  • 豊かな環境飼育は胎仔期バルプロ酸曝露マウスの自閉症様行動を抑制する  [Not invited]
    田熊 一敞; 山口 浩史; 原 雄大; 吾郷 由希夫; 喜多 恵利加; 長谷部 茂; 中澤 敬信; 橋本 均; 松田 敏夫
    第92回日本薬理学会年会  2019/03
  • 妊娠マウスへのバルプロ酸投与は胎仔脳においてmiR-132を増加させる  [Not invited]
    中澤 敬信; 原 雄大; 吾郷 由希夫; 喜多 恵利加; 長谷部 茂; 橋本 均; 松田 敏夫; 田熊 一敞
    第92回日本薬理学会年会  2019/03
  • 新規抗ASCT2モノクローナル抗体はKRAS遺伝子変異ヒト癌細胞の増殖を阻害する  [Not invited]
    原 雄大; 吉本 蒼司; 益子 高
    第92回日本薬理学会年会  2019/03
  • 前頭葉を標的とする自閉症スペクトラム 障害の新たな治療戦略の可能性  [Not invited]
    田熊 一敞; 原 雄大; 吾郷 由希夫; 橋本 均; 中澤 敬信; 松田 敏夫
    第28回日本臨床精神神経薬理学会・第48回日本神経精神薬理学会  2018/11
  • ドパミン神経系賦活化薬の慢性投与は自閉症モデルマウスの行動異常を改善する  [Not invited]
    原 雄大; 吾郷 由希夫; 長谷部 茂; 中澤 敬信; 橋本 均; 松田 敏夫; 田熊 一敞
    第68回日本薬学会近畿支部総会・大会  2018/10
  • HER3およびMETの阻害によるヒト大腸癌の治療効果に関する検討  [Not invited]
    山崎 晶貴; 原 雄大; 益子 高
    第77回日本癌学会学術総会  2018/09
  • CRISPR/Cas9遺伝子破壊に基づく癌遺伝子産物間クロストーク  [Not invited]
    三宅 陸斗; 山崎 晶貴; 原 雄大; 益子 高
    第77回日本癌学会学術総会  2018/09
  • 新規抗ASCT2モノクローナル抗体のヒト大腸癌に対する抗癌効果  [Not invited]
    原 雄大; 益子 高
    第77回日本癌学会学術総会  2018/09
  • Effects of intranasal oxytocin on autism-like behavioral abnormalities in valproic acid-induced mouse model of autism  [Not invited]
    Yuta Hara; Yukio Ago; Momoko Higuchi; Shigeru Hasebe; Takanobu Nakazawa; Hitoshi Hashimoto; Toshio Matsuda; Kazuhiro Takuma
    第91回日本薬理学会年会/18th World Congress of Basic and Clinical Pharmacology  2018/07
  • ASCT2アミノ酸トランスポーターに対するモノクローナル抗体作製とその抗腫瘍活性性の評価  [Not invited]
    原 雄大; 南 侑志; 吉本 蒼司; 益子 高
    日本薬学会第138年会  2018/03
  • 自閉スペクトラム症モデルマウスの社会性行動障害に有効な抗てんかん作用を有する医薬品の探索  [Not invited]
    三浦 大樹; 笠井 淳司; 彌永 祐輔; 原 雄大; 中澤 敬信; 吾郷 由希夫; 田熊 一敞; 橋本 均
    第132回日本薬理学会近畿支部会  2017/11
  • 繊維芽細胞増殖因子19（FGF19）に対するモノクローナル抗体作製  [Not invited]
    原 雄大; 上田 詩歩; 山崎 晶貴; 藤田 健一; 西尾 和人; 益子 高
    第76回日本癌学会学術総会  2017/09
  • ドパミン神経賦活薬の慢性投与は胎仔期バルプロ酸曝露マウスの自閉症様行動を改善する  [Not invited]
    長谷部 茂; 原 雄大; 樋口 桃子; 吾郷 由希夫; 中澤 敬信; 橋本 均; 松田 敏夫; 田熊 一敞
    第38回日本生物学的精神医学会・第59回 日本神経化学会大会 合同年会  2016/09
  • 発育期環境要因による神経精神疾患の発症制御  [Not invited]
    田熊 一敞; 長谷部 茂; 原 雄大; 中澤 敬信; 橋本 均; 松田 敏夫; 吾郷 由希夫
    第38回日本生物学的精神医学会・第59回 日本神経化学会大会 合同年会  2016/09
  • 自閉症モデルマウスにおける前頭前皮質ドパミン神経系の異常～ADHD治療薬による行動異常の改善  [Not invited]
    吾郷 由希夫; 原 雄大; 前田 優子; 長谷部 茂; 橋本 均; 松田 敏夫; 田熊 一敞
    第46回日本神経精神薬理学会年会  2016/07
  • 胎仔期のヒストン脱アセチル化酵素阻害薬曝露による雄性マウス生育後の情動行動、脳組織形態への影響  [Not invited]
    原 雄大; 吾郷 由希夫; 片芝 圭亮; 樽田 淳樹; 樋口 桃子; 尾中 勇祐; 橋本 均; 松田 敏夫; 田熊 一敞
    第89回日本薬理学会年会  2016/03
  • 注意欠陥多動性障害治療薬による前頭葉ドパミン神経活性化を介した胎仔期バルプロ酸曝露マウスの行動異常の改善  [Not invited]
    原 雄大; 吾郷 由希夫; 樽田 淳樹; 片芝 圭亮; 樋口 桃子; 長谷部 茂; 尾中 勇祐; 橋本 均; 松田 敏夫; 田熊 一敞
    第128回日本薬理学会近畿部会  2015/11
  • 前頭前皮質ドパミン神経系の活性化による胎仔期バルプロ酸曝露マウス行動異常の改善  [Not invited]
    原 雄大; 樽田 淳樹; 片芝 圭亮; 樋口 桃子; 東野 功典; 橋本 均; 松田 敏夫; 吾郷 由希夫; 田熊 一敞
    第58回日本神経化学会大会  2015/09
  • 胎仔期バルプロ酸曝露は雄性マウス前頭皮質のドパミン神経機能を低下させる  [Not invited]
    原 雄大; 高野 恵利加; 樽田 淳樹; 片芝 圭亮; 東野 功典; 吾郷 由希夫; 松田 敏夫; 田熊 一敞
    日本薬学会第135年会  2015/03
  • 胎仔期バルプロ酸曝露マウスの前頭葉ドパミン神経系異常  [Not invited]
    原 雄大; 高野 恵利加; 片芝 圭亮; 樽田 淳樹; 東野 功典; 前田 優子; 吾郷 由希夫; 田熊 一敞; 松田 敏夫
    第24回日本臨床精神神経薬理学会・第44回日本神経精神薬理学会合同年会  2014/11
  • 胎仔期のバルプロ酸曝露は成体期におけるメタンフェタミン感受性の低下を引き起こす  [Not invited]
    原 雄大; 高野 恵利加; 片芝圭亮; 樽田 淳樹; 東野 功典; 前田 優子; 吾郷 由希夫; 田熊 一敞; 松田 敏夫
    第37回日本神経科学大会  2014/09
  • Prenatal exposure to valproic acid causes sex-dependent behavioral abnormalities and cortical pathology in mice  [Not invited]
    Yuta Hara; Shunsuke Kataoka; Yuko Maeda; Erika Takano; Yukio Ago; Kazuhiro Takuma; Toshio Matsuda
    The 43rd annual meeting of the Society for Neuroscience (Neuroscience 2013)  2013/11
  • 胎仔期バルプロ酸曝露マウスの生育後の行動異常発現および皮質構造変化における性差  [Not invited]
    原 雄大; 片岡 駿介; 前田 優子; 吾郷 由希夫; 田熊 一敞; 松田 敏夫
    第85回日本薬理学会年会  2012/03
  • マウス胎仔期バルプロ酸曝露による自閉症様行動の発現および大脳皮質層構造変化におけるヒストンアセチル化の関与  [Not invited]
    原 雄大; 片岡 駿介; 前田 優子; 吾郷 由希夫; 田熊 一敞; 松田 敏夫
    第54回日本神経化学会大会  2011/09

MISC

Awards & Honors

  • 2021/02 大阪対がん協会 2020年度がん研究助成奨励金
     グリオーマ病態におけるケモカイン受容体CCR4陽性Th17細胞の脳内浸潤の意義 
    受賞者: 原 雄大
  • 2018/12 平成30年度日本薬学会近畿支部奨励賞
     ドパミン神経系賦活化薬の慢性投与は自閉症モデルマウスの行動異常を改善する 
    受賞者: 原 雄大

Research Grants & Projects

  • 日本学術振興会：科学研究費助成事業
    Date (from‐to) : 2023/04 -2026/03 
    Author : 中山 隆志; 原 雄大; 松尾 一彦
  • 日本学術振興会：科学研究費助成事業
    Date (from‐to) : 2023/04 -2026/03 
    Author : 原 雄大
  • 日本学術振興会：科学研究費助成事業
    Date (from‐to) : 2021/04 -2023/03 
    Author : 原 雄大
     
    脳腫瘍の1種であるグリオーマは、治療薬がほとんど無く、手術での除去も困難なことより、極めて難治性である。様々ながん種において、制御性T細胞（Treg）やTh17細胞などのT細胞サブセットの果たす役割が解明されつつあるが、グリオーマ患者ではそれら細胞の脳および腫瘍への浸潤が報告されているものの、病態に及ぼす影響については未だ不明である。 TregやTh17細胞には、ケモカイン受容体CCR4が発現しており、これら細胞の遊走に関わる主要な制御因子として知られている。グリオーマ患者脳内では、CCR4のリガンドであるCCL17の発現が報告されていることより、CCR4を介してTregやTh17細胞が脳内へと浸潤していると考えられるが、浸潤機序の詳細は未だ不明である。 本研究課題では、グリオーマにおけるCCR4の寄与について解明することを目的としている。 マウスグリオーマ細胞株CT-2Aを脳内に投与し、グリオーマモデルマウスを作製した。まず、CCL17発現をELISA法および免疫染色法にて解析した。正常マウスの脳および腫瘍周辺の脳組織と比較し、腫瘍においてCCL17の発現が顕著に増加した。また、CCL17は、血管内皮細胞やマクロファージ/ミクログリアより産生されていることを見出した。続いて、CCR4の寄与について検討するため、CCR4欠損マウスを用いてモデルマウスを作製した。CCR4欠損マウスは、野生型マウスと比較し、腫瘍の増殖が有意に亢進した。脳内への浸潤細胞をフローサイトメトリー法により解析したところ、Tregや細胞傷害性T細胞には変化は認められなかったが、Th17細胞の割合がCCR4欠損マウスで有意に減少した。本成績より、グリオーマにおいて、CCR4はTh17細胞の遊走を介して腫瘍増殖に影響している可能性が示された。
  • グリオーマ病態におけるケモカイン受容体CCR4陽性Th17細胞の脳内浸潤の意義
    大阪対がん協会 2020年度がん研究助成奨励金：
    Date (from‐to) : 2021/04 -2022/03 
    Author : 原 雄大
  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research
    Date (from‐to) : 2019/04 -2021/03 
    Author : Hara Yuta
     
    Mutations in KRAS are detected in various human cancers. However, there are few effective drugs for KRAS-mutated cancers. Glutamine is thought to be one of the pivotal nutrients for proliferation and survival of cancer cells. ASCT2 (SLC1A5) is a multi-pass transmembrane protein that transports neutral amino acids. ASCT2 is reported to be highly expressed in many cancer cells, and is thought to work as a major transporter for glutamine. We have developed a novel monoclonal antibody (mAb) against the extracellular domain of human ASCT2. In the present study, we examined the effects of the mAb on KRAS-mutated colorectal cancer cells. Treatment with anti-ASCT2 mAb decreased the concentration of intracellular glutamine and in vivo tumor growth. However, these effects were not observed in colorectal cancer cells which harbor wild-type KRAS. These results suggest that ASCT2 is a promising therapeutic target for KRAS-mutated cancers.
  • 日本学術振興会：科学研究費助成事業
    Date (from‐to) : 2013/04 -2016/03 
    Author : 原 雄大
     
    抗てんかん薬であるバルプロ酸(VPA)の妊娠期の服用が、出生児の自閉症発症リスクを増大させることから、胎生期にVPAを曝露した動物が自閉症のモデル動物として汎用されている。当研究室において、胎生12.5日目にVPAを投与したマウスが自閉症様行動異常を示すことを見出している。 昨年度までに、VPA曝露マウスの前頭前皮質においてドパミン(DA)神経系機能が低下していること、ならびに前頭前皮質のDA神経系を活性化する注意欠陥多動性障害(ADHD)治療薬の慢性投与により、VPA曝露マウスの行動異常および前頭前皮質における樹状突起スパイン密度の低下が改善することを見出している。 ADHD治療薬による改善効果におけるDA神経系の役割を調べるために、DA-D1、D2、アドレナリンα2受容体拮抗薬がADHD治療薬による改善効果に及ぼす影響を検討した。D1受容体拮抗薬もしくはD2受容体拮抗薬をそれぞれADHD治療薬と併用投与した際、社会性行動障害、認知記憶障害、前頭前皮質のスパイン密度低下に対する改善効果は消失した。一方、α2受容体拮抗薬の併用投与では、ADHD治療薬の改善効果に影響を与えなかった。 さらに、抗精神病薬による改善効果についても検討した。非定型抗精神病薬であるリスペリドン、アリピプラゾールは前頭前皮質のDA神経系を活性化することが報告されている。これら2剤をそれぞれVPA曝露マウスに慢性投与したところ、ADHD治療薬と同様に、行動異常ならびにスパイン密度の低下が改善した。また、前頭前皮質のDA神経系に対する活性化作用を有しない抗精神病薬であるハロペリドールでは改善効果は認められなかった。以上の成績は、前頭前皮質のドパミン神経系の慢性的な活性化が自閉症の新しい治療機序となる可能性を示している。

Others

  • 2021/08 -2022/03  肺組織への免疫細胞の遊走機構の解明 
    令和3年度“オール近大”新型コロナウイルス感染症対策支援プロジェクト
  • 2021/04 -2022/03  ケモカイン受容体CCR4を介したTh17細胞の脳内への浸潤がグリオーマに与える影響 
    近畿大学学内研究助成金 奨励研究助成金 (課題番号SR02)
  • 2018/04 -2019/03  癌遺伝子産物HER3-MET複合体を標的としたヒト大腸癌の新規併用療法の開発 
    近畿大学学内研究助成金 奨励研究助成金 (課題番号SR06)

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