笹部　潤平 （ササベ　ジュンペイ）

SASABE Jumpei

写真a

所属（所属キャンパス）

医学部 電子顕微鏡研究室 （信濃町）

職名

准教授（有期）

メールアドレス

メールアドレス

HP

研究室住所

東京都新宿区信濃町３５　予防医学校舎１F

研究室電話番号

03-5363-3772
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経歴 【 表示 ／ 非表示 】

  • 2002年04月
    -
    2004年03月

    慶應義塾大学病院, 内科学, 研修医

  • 2008年04月
    -
    2010年03月

    慶應義塾大学医学部, 解剖学, 特別研究助教

  • 2010年04月
    -
    2016年03月

    慶應義塾大学医学部, 解剖学, 助教

  • 2013年10月
    -
    2015年08月

    Brigham and Women's Hospital / Harvard Medical School / HHMI, Microbiology and Immunology, Postdoctoral fellow / Research fellow

  • 2016年04月
    -
    2017年12月

    慶應義塾大学医学部, 解剖学, 専任講師

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学歴 【 表示 ／ 非表示 】

  • 1996年04月
    -
    2002年03月

    慶應義塾大学, 医学部

    卒業

  • 2004年04月
    -
    2008年03月

    慶應義塾大学, 医学部医学研究科博士過程, 医学研究科・生理系専攻

    大学院, 修了, 博士

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学位 【 表示 ／ 非表示 】

  • 博士号（医学）, 慶應義塾大学

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免許・資格 【 表示 ／ 非表示 】

  • 医師免許

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研究分野 【 表示 ／ 非表示 】

  • ライフサイエンス / 機能生物化学

  • ライフサイエンス / 神経科学一般

  • ライフサイエンス / 薬理学

  • ライフサイエンス / 医化学

  • ライフサイエンス / 免疫学

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研究キーワード 【 表示 ／ 非表示 】

  • D-アミノ酸

  • キラル生物学

  • 宿主-微生物相互作用

  • 微生物・免疫学

  • 生化学

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論文 【 表示 ／ 非表示 】

  • Plasma d-asparagine and the d/l-serine ratio reflect chronic kidney diseases in children regardless of physique

    Morishita T., Nishizaki N., Taniguchi S., Sakai S., Kimura T., Mita M., Nakagawa M., Endo A., Ohtomo Y., Yasui M., Shimizu T., Sasabe J.

    Amino Acids 56 （ 1 ）  2024年12月

    ISSN  09394451

    　概要を見る

    Biomarkers that accurately reflect renal function are essential in management of chronic kidney diseases (CKD). However, in children, age/physique and medication often alter established renal biomarkers. We studied whether amino acid enantiomers in body fluids correlate with renal function and whether they are influenced by physique or steroid medication during development. We conducted a prospective study of children 2 to 18 years old with and without CKD. We analyzed associations of serine/asparagine enantiomers in body fluids with major biochemical parameters as well as physique. To study consequences of kidney dysfunction and steroids on serine/asparagine enantiomers, we generated juvenile mice with uninephrectomy, ischemic reperfusion injury, or dexamethasone treatment. We obtained samples from 27 children, of which 12 had CKD due to congenital (n = 7) and perinatal (n = 5) causes. Plasma d-asparagine and the d/l-serine ratio had robust, positive linear associations with serum creatinine and cystatin C, and detected CKD with high sensitivity and specificity, uninfluenced by body size or biochemical parameters. In the animal study, kidney dysfunction increased plasma d-asparagine and the d/l-serine ratio, but dexamethasone treatment did not. Thus, plasma d-asparagine and the d/l-serine ratio can be useful markers for renal function in children.

  • Sodium benzoate attenuates 2,8-dihydroxyadenine nephropathy by inhibiting monocyte/macrophage TNF-α expression

    Oshima Y., Wakino S., Kanda T., Tajima T., Itoh T., Uchiyama K., Yoshimoto K., Sasabe J., Yasui M., Itoh H.

    Scientific Reports 13 （ 1 ）  2023年12月

    　概要を見る

    Sodium benzoate (SB), a known D-amino acid oxidase (DAO) enzyme inhibitor, has an anti-inflammatory effect, although its role in renal damage has not been explored. 2,8-dihydroxyadenine crystal induced chronic kidney disease, in which TNF-α is involved in the pathogenesis, was established by oral adenine administration in C57BL/6JJcl mice (AdCKD) with or without SB to investigate its renal protective effects. SB significantly attenuated AdCKD by decreasing serum creatinine and urea nitrogen levels, and kidney interstitial fibrosis and tubular atrophy scores. The survival of AdCKD mice improved 2.6-fold by SB administration. SB significantly decreased the number of infiltrating macrophages observed in the positive F4/80 immunohistochemistry area and reduced the expression of macrophage markers and inflammatory genes, including TNF-α, in the kidneys of AdCKD. Human THP-1 cells stimulated with either lipopolysaccharide or TNF-α showed increased expression of inflammatory genes, although this was significantly reduced by SB, confirming the anti-inflammatory effects of SB. SB exhibited renal protective effects in AdCKD in DAO enzyme deficient mice, suggesting that anti-inflammatory effect of SB was independent of DAO enzyme activity. Moreover, binding to motif DNA sequence, protein level, and mRNA level of NF-κB RelB were significantly inhibited by SB in AdCKD kidneys and lipopolysaccharide treated THP-1 cells, respectively. We report that anti-inflammatory property of SB is independent of DAO enzymatic activity and is associated with down regulated NF-κB RelB as well as its downstream inflammatory genes such as TNF-α in AdCKD.

  • Homeostasis of serine enantiomers is disrupted in the post-mortem caudate putamen and cerebrospinal fluid of living Parkinson's disease patients

    Di Maio A., Nuzzo T., Gilio L., Serra M., Buttari F., Errico F., De Rosa A., Bassi M.S., Morelli M., Sasabe J., Sulzer D., Carta M., Centonze D., Usiello A.

    Neurobiology of Disease 184 2023年08月

    ISSN  09699961

    　概要を見る

    L-serine generated in astrocytes plays a pivotal role in modulating essential neurometabolic processes, while its enantiomer, D-serine, specifically regulates NMDA receptor (NMDAR) signalling. Despite their physiological relevance in modulating cerebral activity, serine enantiomers metabolism in Parkinson's disease (PD) remains elusive. Using High-Performance Liquid Chromatography (HPLC), we measured D- and L-serine levels along with other amino acids known to modulate NMDAR function, such as L-glutamate, L-aspartate, D-aspartate, and glycine, in the post-mortem caudate putamen (CPu) and superior frontal gyrus (SFG) of PD patients. Moreover, we examined these amino acids in the cerebrospinal fluid (CSF) of de novo living PD, Alzheimer's disease (AD), and amyotrophic lateral sclerosis (ALS) patients versus subjects with other neurological disorders (OND), used as control. We found higher D-serine and L-serine levels in the CPu of PD patients but not in the SFG, a cerebral region that, in contrast to the CPu, is not innervated by nigral dopaminergic terminals. We also highlighted a significant elevation of both serine enantiomers in the CSF samples from PD but not in those of AD and ALS patients, compared with control subjects. By contrast, none or only minor changes were found in the amount of other NMDAR modulating amino acids. Our findings identify D-serine and L-serine level upregulation as a biochemical signature associated with nigrostriatal dopaminergic degeneration in PD.

  • Mammals sustain amino acid homochirality against chiral conversion by symbiotic microbes

    Gonda Y., Matsuda A., Adachi K., Ishii C., Suzuki M., Osaki A., Mita M., Nishizaki N., Ohtomo Y., Shimizu T., Yasui M., Hamase K., Sasabe J.

    Proceedings of the National Academy of Sciences of the United States of America 120 （ 15 ）  2023年04月

    ISSN  00278424

    　概要を見る

    Mammals exhibit systemic homochirality of amino acids in L-configurations. While ribosomal protein synthesis requires rigorous chiral selection for L-amino acids, both endogenous and microbial enzymes convert diverse L-amino acids to D-configurations in mammals. However, it is not clear how mammals manage such diverse D-enantiomers. Here, we show that mammals sustain systemic stereo dominance of L-amino acids through both enzymatic degradation and excretion of D-amino acids. Multidimensional high performance liquidchromatography analyses revealed that in blood, humans and mice maintain D-amino acids at less than several percent of the corresponding L-enantiomers, while D-amino acids comprise ten to fifty percent of the L-enantiomers in urine and feces. Germ-free experiments showed that vast majority of D-amino acids, except for D-serine, detected in mice are of microbial origin. Experiments involving mice that lack enzymatic activity to catabolize D-amino acids showed that catabolism is central to the elimination of diverse microbial D-amino acids, whereas excretion into urine is of minor importance under physiological conditions. Such active regulation of amino acid homochirality depends on maternal catabolism during the prenatal period, which switches developmentally to juvenile catabolism along with the growth of symbiotic microbes after birth. Thus, microbial symbiosis largely disturbs homochirality of amino acids in mice, whereas active host catabolism of microbial D-amino acids maintains systemic predominance of L-amino acids. Our findings provide fundamental insight into how the chiral balance of amino acids is governed in mammals and further expand the understanding of interdomain molecular homeostasis in host-microbial symbiosis.

  • Endogenous D-serine exists in the mammalian brain independent of synthesis by serine racemase

    Osaki A., Aoyama M., Mita M., Hamase K., Yasui M., Sasabe J.

    Biochemical and Biophysical Research Communications 641   186 - 191 2023年01月

    ISSN  0006291X

    　概要を見る

    Activation of N-methyl-D-aspartate receptors (NMDARs) requires binding of a co-agonist in addition to L-glutamate. D-serine binds to the co-agonist site on GluN1 subunits of NMDARs and modulates glutamatergic neurotransmission. While loss of GluN1 subunits in mice results in neonatal death due to respiratory failure, animals that lack a D-serine synthetic enzyme, serine racemase (SR), show grossly normal growth. However, SR-independent origins of D-serine in the brain remain unclarified. In the present study, we investigated the origin of brain D-serine in mice. Loss of SR significantly reduced D-serine in the cerebral cortex, but a portion of D-serine remained in both neonates and adults. Although D-serine was also produced by intestinal bacteria, germ-free experiments did not influence D-serine levels in the cerebral cortex. In addition, treatment of SR-knockout mice with antibiotics showed a significant reduction of intestinal D-serine, but no reduction in the brain. On the other hand, restriction of dietary intake reduced systemic circulation of D-serine and resulted in a slight decrease of D-serine in the cerebral cortex, but did not account for brain D-serine found in the SR-knockout mice. Therefore, our findings show that endogenous D-serine of non-SR origin exists in the brain. Such previously unrecognized, SR-independent, endogenous D-serine may contribute baseline activity of NMDARs, especially in developing brain, which has minimal SR expression.

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KOARA（リポジトリ）収録論文等 【 表示 ／ 非表示 】

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総説・解説等 【 表示 ／ 非表示 】

  • Astrocytic d-amino acid oxidase degrades d-serine in the hindbrain

    Gonda Y., Ishii C., Mita M., Nishizaki N., Ohtomo Y., Hamase K., Shimizu T., Sasabe J.

    FEBS Letters （FEBS Letters）   2022年

    ISSN  00145793

    　概要を見る

    d-Serine modulates excitatory neurotransmission by binding to N-methyl-d-aspartate glutamate receptors. d-Amino acid oxidase (DAO) degrades d-amino acids, such as d-serine, in the central nervous system, and is associated with neurological and psychiatric disorders. However, cell types that express brain DAO remain controversial, and whether brain DAO influences systemic d-amino acids in addition to brain d-serine remains unclear. Here, we created astrocyte-specific DAO-conditional knockout mice. Knockout in glial fibrillary acidic protein-positive cells eliminated DAO expression in the hindbrain and increased d-serine levels significantly in the cerebellum. Brain DAO did not influence levels of d-amino acids in the forebrain or periphery. These results show that astrocytic DAO regulates d-serine specifically in the hindbrain.

  • Editorial: Bioscience of D-amino acid oxidase from biochemistry to pathophysiology

    Pollegioni L., Sasabe J.

    Frontiers in Molecular Biosciences （Frontiers in Molecular Biosciences）  5 （ NOV ）  2018年11月

  • Emerging role of D-Amino acid metabolism in the innate defense

    Sasabe J., Suzuki M.

    Frontiers in Microbiology （Frontiers in Microbiology）  9 （ MAY ）  2018年05月

    　概要を見る

    © 2018 Sasabe and Suzuki. Mammalian innate and adaptive immune systems use the pattern recognition receptors, such as toll-like receptors, to detect conserved bacterial and viral components. Bacteria synthesize diverse D-amino acids while eukaryotes and archaea generally produce two D-amino acids, raising the possibility that many of bacterial D-amino acids are bacteria-specific metabolites. Although D-amino acids have not been identified to bind to any known pattern recognition receptors, D-amino acids are enantioselectively recognized by some other receptors and enzymes including a flavoenzyme D-amino acid oxidase (DAO) in mammals. At host-microbe interfaces in the neutrophils and intestinal mucosa, DAO catalyzes oxidation of bacterial D-amino acids, such as D-alanine, and generates H2O2, which is linked to antimicrobial activity. Intestinal DAO also modifies the composition of microbiota through modulation of growth for some bacteria that are dependent on host nutrition. Furthermore, regulation and recognition of D-amino acids in mammals have additional meanings at various host-microbe interfaces; D-phenylalanine and D-tryptophan regulate chemotaxis of neutrophils through a G-coupled protein receptor, D-serine has a bacteriostatic role in the urinary tract, D-phenylalanine and D-leucine inhibit innate immunity through the sweet taste receptor in the upper airway, and D-tryptophan modulates immune tolerance in the lower airway. This mini-review highlights recent evidence supporting the hypothesis that D-amino acids are utilized as inter-kingdom communication at host-microbe interface to modulate bacterial colonization and host defense.

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競争的研究費の研究課題 【 表示 ／ 非表示 】

  • セリンのキラリティによる脱髄性疾患の病態制御機構の検討

    2024年06月
    -
    2026年03月

    笹部 潤平, 挑戦的研究（萌芽）, 補助金,  研究代表者

  • D-アミノ酸による細胞内代謝調節機構と細胞増殖制御

    2022年06月
    -
    2024年03月

    文部科学省・日本学術振興会, 科学研究費助成事業, 笹部 潤平, 挑戦的研究（萌芽）, 補助金,  研究代表者

  • 共生細菌が調節するアミノ酸キラリティによる宿主エネルギー代謝機構の解明

    2021年04月
    -
    2026年03月

    文部科学省・日本学術振興会, 科学研究費助成事業, 笹部 潤平, 基盤研究(B), 補助金,  研究代表者

  • 小腸粘膜防御因子DAOの腸内細菌と宿主による制御機構の解明

    2016年04月
    -
    2019年03月

    文部科学省・日本学術振興会, 科学研究費助成事業, 笹部　潤平, 基盤研究(C), 補助金,  研究代表者

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受賞 【 表示 ／ 非表示 】

  • 慶應医学賞研究奨励賞

    2017年

  • Best Presentation Award Boston Bacterial Meeting 2015

    2015年, Harvard Medical School

  • 慶應義塾大学三四会奨励賞

    2012年

  • D-アミノ酸学会奨励賞

    2012年

  • 慶應義塾大学塾長賞

    2008年

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担当授業科目 【 表示 ／ 非表示 】

  • 人体の生理

    2025年度

  • 薬理学

    2025年度

  • 薬理学

    2024年度

  • 薬理学

    2023年度

  • 薬理学

    2022年度

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担当経験のある授業科目 【 表示 ／ 非表示 】

  • 薬理学

    慶應義塾

    2018年04月
    -
    継続中
    , 

    秋学期, 講義, 専任

  • 基礎分子細胞生物学

    慶應義塾

    2018年04月
    -
    2022年03月
    , 

    秋学期, 講義

  • 生化学

    慶應義塾

    2018年04月
    -
    2019年03月
    , 

    秋学期, 講義

  • 組織学

    慶應義塾

    2010年04月
    -
    2017年03月
    , 

    春学期, 講義

  • 解剖学

    慶應義塾大学

    2010年04月
    -
    2017年03月
    , 

    学部専門科目, 実習・実験, 専任

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所属学協会 【 表示 ／ 非表示 】

  • 日本薬理学会

    　

  • 日本生化学会

    　

  • D-アミノ酸学会

    　
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委員歴 【 表示 ／ 非表示 】

  • 2017年04月
    -
    継続中

    運営委員, D-アミノ酸学会

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