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 薬理学教室 (信濃町)

職名

専任講師(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 総合医科学研究棟6S1

研究室電話番号

03-5363-3750

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, 特別研究助教

  • 2010年04月
    -
    2016年03月

    慶應義塾大学医学部, 助教

  • 2013年10月
    -
    2015年08月

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

  • 2016年04月
    -
    継続中

    慶應義塾大学医学部, 専任講師(学部内)

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

学位 【 表示 / 非表示

  • 博士号(医学), 慶應義塾大学

免許・資格 【 表示 / 非表示

  • 医師免許

 

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

研究キーワード 【 表示 / 非表示

  • D-アミノ酸

  • キラル生物学

  • 神経変性疾患

  • 自然免疫

 

論文 【 表示 / 非表示

  • Chiral resolution of plasma amino acids reveals enantiomer-selective associations with organ functions

    Suzuki M., Shimizu-Hirota R., Mita M., Hamase K., Sasabe J.

    Amino Acids (Amino Acids)  54 ( 3 ) 421 - 432 2022年03月

    ISSN  09394451

     概要を見る

    Plasma amino acids reflect the dynamics of amino acids in organs and their levels have clinical significance. Amino acids as clinical indicators have been evaluated as a mixture of d- and l-amino acids because d-enantiomers are believed to be physiologically nonexistent. However, it has become clear that some d-amino acids are synthesized by endogenous enzymes and symbiotic bacteria. Here, using a two-dimensional HPLC system, we measured enantiomers of all proteinogenic amino acids in plasma and urine and analyzed for correlation with other biochemical parameters in humans who underwent health checkups at our institutional hospital. Four d-amino acids (d-asparagine, d-alanine, d-serine, and d-proline) were detected in the plasma, amounting to less than 1% of the quantities of l-amino acids, but in the urine at several tens of percent, showing that d-amino acids have much higher fractional excretion than their L-counterparts. Detected plasma d-amino acids and d-/l-amino acid ratios were well correlated with renal parameters, such as blood urea nitrogen, creatinine, and cystatin C. On the other hand, a set of plasma l-amino acids were associated with body mass index and correlated with metabolic parameters such as liver enzymes, lipids, blood glucose, and uric acid. Thus, chiral resolution of plasma amino acids revealed totally different associations of the enantiomers with organ functions, and warrants further investigation for clinical and laboratory usefulness.

  • Increased listeria monocytogenes dissemination and altered population dynamics in Muc2-deficient mice

    Zhang T., Sasabe J., Hullahalli K., Sit B., Waldor M.K.

    Infection and Immunity (Infection and Immunity)  89 ( 4 )  2021年04月

    ISSN  00199567

     概要を見る

    The mucin Muc2 is a major constituent of the mucus layer that covers the intestinal epithelium and creates a barrier between epithelial cells and luminal commensal or pathogenic microorganisms. The Gram-positive foodborne pathogen Listeria monocytogenes can cause enteritis and also disseminate from the intestine to give rise to systemic disease. L. monocytogenes can bind to intestinal Muc2, but the influence of the Muc2 mucin barrier on L. monocytogenes intestinal colonization and systemic dissemination has not been explored. Here, we used an orogastric L. monocytogenes infection model to investigate the role of Muc2 in host defense against L. monocytogenes. Compared to wild-type mice, we found that Muc22/2 mice exhibited heightened susceptibility to orogastric challenge with L. monocytogenes, with higher mortality, elevated colonic pathology, and increased pathogen burdens in both the intestinal tract and distal organs. In contrast, L. monocytogenes burdens were equivalent in wild-type and Muc22/2 animals when the pathogen was administered intraperitoneally, suggesting that systemic immune defects related to Muc2 deficiency do not explain the heightened pathogen dissemination observed in oral infections. Using a barcoded L. monocytogenes library to measure intrahost pathogen population dynamics, we found that Muc22/2 animals had larger pathogen founding population sizes in the intestine and distal sites than observed in wild-type animals. Comparisons of barcode frequencies suggested that the colon becomes the major source for seeding the internal organs in Muc22/2 animals. Together, our findings reveal that Muc2 mucin plays a key role in controlling L. monocytogenes colonization, dissemination, and population dynamics.

  • Host-microbe cross-talk governs amino acid chirality to regulate survival and differentiation of B cells

    Suzuki M., Sujino T., Chiba S., Harada Y., Goto M., Takahashi R., Mita M., Hamase K., Kanai T., Ito M., Waldor M.K., Yasui M., Sasabe J.

    Science Advances (Science Advances)  7 ( 10 )  2021年03月

     概要を見る

    Organisms use l-amino acids (l-aa) for most physiological processes. Unlike other organisms, bacteria chiral-convert l-aa to d-configurations as essential components of their cell walls and as signaling molecules in their ecosystems. Mammals recognize microbe-associated molecules to initiate immune responses, but roles of bacterial d-amino acids (d-aa) in mammalian immune systems remain largely unknown. Here, we report that amino acid chirality balanced by bacteria-mammal cross-talk modulates intestinal B cell fate and immunoglobulin A (IgA) production. Bacterial d-aa stimulate M1 macrophages and promote survival of intestinal naïve B cells. Mammalian intestinal d-aa catabolism limits the number of B cells and restricts growth of symbiotic bacteria that activate T cell–dependent IgA class switching of the B cells. Loss of d-aa catabolism results in excessive IgA production and dysbiosis with altered IgA coating on bacteria. Thus, chiral conversion of amino acids is linked to bacterial recognition by mammals to control symbiosis with bacteria.

  • Serum d-serine accumulation after proximal renal tubular damage involves neutral amino acid transporter Asc-1

    Suzuki M., Gonda Y., Yamada M., Vandebroek A.A., Mita M., Hamase K., Yasui M., Sasabe J.

    Scientific Reports (Scientific Reports)  9 ( 1 )  2019年12月

     概要を見る

    Chiral separation has revealed enantio-specific changes in blood and urinary levels of amino acids in kidney diseases. Blood d-/l-serine ratio has been identified to have a correlation with creatinine-based kidney function. However, the mechanism of distinctive behavior in serine enantiomers is not well understood. This study was performed to investigate the role of renal tubules in derangement of serine enantiomers using a mouse model of cisplatin-induced tubular injury. Cisplatin treatment resulted in tubular damage histologically restricted to the proximal tubules and showed a significant increase of serum d-/l-serine ratio with positive correlations to serum creatinine and blood urine nitrogen (BUN). The increased d-/l-serine ratio did not associate with activity of a d-serine degrading enzyme, d-amino acid oxidase, in the kidney. Screening transcriptions of neutral amino acid transporters revealed that Asc-1, found in renal tubules and collecting ducts, was significantly increased after cisplatin-treatment, which correlates with serum d-serine increase. In vitro study using a kidney cell line showed that Asc-1 is induced by cisplatin and mediated influx of d-serine preferably to l-serine. Collectively, these results suggest that cisplatin-induced damage of proximal tubules accompanies Asc-1 induction in tubules and collecting ducts and leads to serum d-serine accumulation.

  • Distinctive roles of d-Amino acids in the homochiral world: Chirality of amino acids modulates mammalian physiology and pathology

    笹部 潤平

    Keio Journal of Medicine (Keio Journal of Medicine)  68 ( 1 ) 1 - 16 2018年05月

    共著, 査読有り,  ISSN  00229717

     概要を見る

    © 2018 by The Keio Journal of Medicine. Living organisms enantioselectively employ l-amino acids as the molecular architecture of protein synthesized in the ribosome. Although l-amino acids are dominantly utilized in most biological processes, accumulating evidence points to the distinctive roles of d-amino acids in non-ribosomal physiology. Among the three domains of life, bacteria have the greatest capacity to produce a wide variety of damino acids. In contrast, archaea and eukaryotes are thought generally to synthesize only two kinds of d-amino acids: d-serine and d-aspartate. In mammals, d-serine is critical for neurotransmission as an endogenous coagonist of N-methyl d-aspartate receptors. Additionally, d-aspartate is associated with neurogenesis and endocrine systems. Furthermore, recognition of d-amino acids originating in bacteria is linked to systemic and mucosal innate immunity. Among the roles played by d-amino acids in human pathology, the dysfunction of neurotransmission mediated by d-serine is implicated in psychiatric and neurological disorders. Non-enzymatic conversion of l-aspartate or l-serine residues to their d-configurations is involved in age-associated protein degeneration. Moreover, the measurement of plasma or urinary d-/l-serine or d-/l-aspartate levels may have diagnostic or prognostic value in the treatment of kidney diseases. This review aims to summarize current understanding of d-amino-acid-associated biology with a major focus on mammalian physiology and pathology.

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KOARA(リポジトリ)収録論文等 【 表示 / 非表示

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.

競争的研究費の研究課題 【 表示 / 非表示

  • 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

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

  • D-アミノ酸学会奨励賞

    2012年

  • 慶應義塾大学三四会奨励賞

    2012年

  • 慶應義塾大学塾長賞

    2008年

 

担当授業科目 【 表示 / 非表示

  • 薬理学

    2022年度

  • MCB

    2022年度

  • 薬理学

    2021年度

  • MCB

    2021年度

  • 薬理学

    2020年度

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担当経験のある授業科目 【 表示 / 非表示

  • 組織学(消化管)

    慶應義塾

    2018年04月
    -
    2019年03月

    春学期, 講義

  • 生化学(アミノ酸光学異性体)

    慶應義塾

    2018年04月
    -
    2019年03月

    秋学期, 講義

  • 薬理学(循環器)

    慶應義塾

    2018年04月
    -
    2019年03月

    秋学期, 講義

  • 基礎分子細胞生物学

    慶應義塾

    2018年04月
    -
    2019年03月

    秋学期, 講義

 

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

     

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