Updated on 2023/05/26


Mizutani Yasuyuki
Nagoya University Hospital Gastroenterology Assistant professor of hospital
Assistant professor of hospital
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Degree 1

  1. 博士(医学) ( 2020.1   名古屋大学 ) 

Research Interests 4

  1. Cancer restraining CAF

  2. Meflin

  3. 膵癌

  4. 癌関連線維芽細胞

Research Areas 2

  1. Life Science / Gastroenterology

  2. Life Science / Tumor biology

Research History 2

  1. Nagoya University   Nagoya University Hospital Gastroenterology   Assistant professor of hospital


  2. Nagoya University   Assistant professor of hospital


Awards 2

  1. Rising Stars in gastroenterology and hepatology from Europe and Japan

    2019.10   United European Gastroenterology Week 2019  

    Yasuyuki Mizutani

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    Award type:Award from international society, conference, symposium, etc. 

  2. 日本膵臓学会学会奨励賞

    2014.7   日本膵臓学会  


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    Award type:Honored in official journal of a scientific society, scientific journal  Country:Japan


Papers 13

  1. Meflin-positive cancer-associated fibroblasts inhibit pancreatic carcinogenesis International coauthorship International journal

    Yasuyuki Mizutani, Hiroki Kobayashi, Tadashi Iida, Naoya Asai, Atsushi Masamune, Akitoshi Hara, Nobutoshi Esaki, Kaori Ushida, Shinji Mii, Yukihiro Shiraki, Kenju Ando, Liang Weng, Seiichiro Ishihara, Suzanne M. Ponik, Matthew W. Conklin, Hisashi Haga, Arata Nagasaka, Takaki Miyata, Makoto Matsuyama, Tomoe Kobayashi, Tsutomu Fujii, Suguru Yamada, Junpei Yamaguchi, Tongtong Wang, Susan L. Woods, Daniel Worthley, Teppei Shimamura, Mitsuhiro Fujishiro, Yoshiki Hirooka, Atsushi Enomoto and Masahide Takahashi

    Cancer Research   Vol. 79 ( 20 ) page: 5367 - 5381   2019.10

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    Language:English   Publishing type:Research paper (scientific journal)  

    DOI: 10.1158/0008-5472.CAN-19-0454



  2. Safety and efficacy of MIKE-1 in patients with advanced pancreatic cancer: a study protocol for an open-label phase I/II investigator-initiated clinical trial based on a drug repositioning approach that reprograms the tumour stroma. Reviewed

    Mizutani Y, Iida T, Ohno E, Ishikawa T, Kinoshita F, Kuwatsuka Y, Imai M, Shimizu S, Tsuruta T, Enomoto A, Kawashima H, Fujishiro M

    BMC cancer   Vol. 22 ( 1 ) page: 205   2022.2

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    Authorship:Lead author   Language:English   Publishing type:Research paper (scientific journal)   Publisher:BMC Cancer  

    Background: Cancer-associated fibroblasts (CAFs) are an important component of the tumour microenvironment. Recent studies revealed CAFs are heterogeneous and CAF subset(s) that suppress cancer progression (cancer-restraining CAFs [rCAFs]) must exist in addition to well-characterised cancer-promoting CAFs (pCAFs). However, the identity and specific markers of rCAFs are not yet reported. We recently identified Meflin as a specific marker of rCAFs in pancreatic and colon cancers. Our studies revealed that rCAFs may represent proliferating resident fibroblasts. Interestingly, a lineage tracing experiment showed Meflin-positive rCAFs differentiate into α-smooth muscle actin-positive and Meflin-negative CAFs, which are generally hypothesised as pCAFs, during cancer progression. Using a pharmacological approach, we identified AM80, a synthetic unnatural retinoid, as a reagent that effectively converts Meflin-negative pCAFs to Meflin-positive rCAFs. We aimed to investigate the efficacy of a combination of AM80 and gemcitabine (GEM) and nab-paclitaxel (nab-PTX) in patients with advanced pancreatic cancer. Methods: The phase I part is a 3 + 3 design, open-label, and dose-finding study. The dose-limiting toxicity (DLT) of these combination therapies would be evaluated for 4 weeks. After the DLT evaluation period, if no disease progression is noted based on the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 or if the patient has no intolerable toxicity, administration of AM80 with GEM and nab-PTX would be continued for up to 24 weeks. The phase II part is an open-label, single-arm study. The maximum tolerated dose (MTD) of AM80 with GEM and nab-PTX, determined in phase I, would be administered until intolerable toxicity or disease progression occurs, up to a maximum of 24 weeks, to confirm efficacy and safety. The primary endpoints are frequency of DLT and MTD of AM80 with GEM and nab-PTX in the phase I part and response rate based on the RECIST in the phase II part. Given the historical control data, we hope that the response rate will be over 23% in phase II. Discussion: Strategies to convert pCAFs into rCAFs have been developed in recent years. We hypothesised that AM80 would be a promising enhancer of chemosensitivity and drug distribution through CAF conversion in the stroma. Trial registration: Clinicaltrial.gov: NCT05064618, registered on 1 October 2021. jRCT: jRCT2041210056, registered on 27 August 2021.

    DOI: 10.1186/s12885-022-09272-2



  3. Pharmacologic conversion of cancer-associated fibroblasts from a protumor phenotype to an antitumor phenotype improves the sensitivity of pancreatic cancer to chemotherapeutics. Reviewed International coauthorship

    Iida T, Mizutani Y, Esaki N, Ponik SM, Burkel BM, Weng L, Kuwata K, Masamune A, Ishihara S, Haga H, Kataoka K, Mii S, Shiraki Y, Ishikawa T, Ohno E, Kawashima H, Hirooka Y, Fujishiro M, Takahashi M, Enomoto A

    Oncogene   Vol. 41 ( 19 ) page: 2764 - 2777   2022.5

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    Authorship:Lead author   Language:English   Publishing type:Research paper (scientific journal)   Publisher:Oncogene  

    Previous therapeutic attempts to deplete cancer-associated fibroblasts (CAFs) or inhibit their proliferation in pancreatic ductal adenocarcinoma (PDAC) were not successful in mice or patients. Thus, CAFs may be tumor suppressive or heterogeneous, with distinct cancer-restraining and -promoting CAFs (rCAFs and pCAFs, respectively). Here, we showed that induced expression of the glycosylphosphatidylinositol-anchored protein Meflin, a rCAF-specific marker, in CAFs by genetic and pharmacological approaches improved the chemosensitivity of mouse PDAC. A chemical library screen identified Am80, a synthetic, nonnatural retinoid, as a reagent that effectively induced Meflin expression in CAFs. Am80 administration improved the sensitivity of PDAC to chemotherapeutics, accompanied by increases in tumor vessel area and intratumoral drug delivery. Mechanistically, Meflin was involved in the suppression of tissue stiffening by interacting with lysyl oxidase to inhibit its collagen crosslinking activity. These data suggested that modulation of CAF heterogeneity may represent a strategy for PDAC treatment.

    DOI: 10.1038/s41388-022-02288-9



  4. Specific characteristics of hemorrhagic Meckel's diverticulum at double-balloon endoscopy Reviewed International journal

    Mizutani Yasuyuki, Nakamura Masanao, Watanabe Osamu, Yamamura Takeshi, Funasaka Kohei, Ohno Eizaburo, Kawashima Hiroki, Miyahara Ryoji, Murino Alberto, Goto Hidemi, Hirooka Yoshiki

    ENDOSCOPY INTERNATIONAL OPEN   Vol. 5 ( 1 ) page: E35-E40   2017.1

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    Authorship:Lead author   Language:English   Publishing type:Research paper (scientific journal)  

    DOI: 10.1055/s-0042-119810

    Web of Science


  5. An unusual cause of obscure gastrointestinal bleeding. Reviewed International journal

    Mizutani Y, Nakamura M, Goto H

    Gastroenterology   Vol. 148 ( 5 ) page: 908-9   2015.5

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    Authorship:Lead author   Language:English   Publishing type:Research paper (scientific journal)  

    DOI: 10.1053/j.gastro.2014.12.048



  6. The Balance of Stromal BMP Signaling Mediated by GREM1 and ISLR Drives Colorectal Carcinogenesis. International coauthorship International journal

    Gastroenterology   Vol. 160 ( 4 ) page: 1224 - 1239.e30   2021.3

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher:Gastroenterology  

    Background & Aims: Cancer-associated fibroblasts (CAFs), key constituents of the tumor microenvironment, either promote or restrain tumor growth. Attempts to therapeutically target CAFs have been hampered by our incomplete understanding of these functionally heterogeneous cells. Key growth factors in the intestinal epithelial niche, bone morphogenetic proteins (BMPs), also play a critical role in colorectal cancer (CRC) progression. However, the crucial proteins regulating stromal BMP balance and the potential application of BMP signaling to manage CRC remain largely unexplored. Methods: Using human CRC RNA expression data, we identified CAF-specific factors involved in BMP signaling, then verified and characterized their expression in the CRC stroma by in situ hybridization. CRC tumoroids and a mouse model of CRC hepatic metastasis were used to test approaches to modify BMP signaling and treat CRC. Results: We identified Grem1 and Islr as CAF-specific genes involved in BMP signaling. Functionally, GREM1 and ISLR acted to inhibit and promote BMP signaling, respectively. Grem1 and Islr marked distinct fibroblast subpopulations and were differentially regulated by transforming growth factor β and FOXL1, providing an underlying mechanism to explain fibroblast biological dichotomy. In patients with CRC, high GREM1 and ISLR expression levels were associated with poor and favorable survival, respectively. A GREM1-neutralizing antibody or fibroblast Islr overexpression reduced CRC tumoroid growth and promoted Lgr5+ intestinal stem cell differentiation. Finally, adeno-associated virus 8 (AAV8)–mediated delivery of Islr to hepatocytes increased BMP signaling and improved survival in our mouse model of hepatic metastasis. Conclusions: Stromal BMP signaling predicts and modifies CRC progression and survival, and it can be therapeutically targeted by novel AAV-directed gene delivery to the liver.

    DOI: 10.1053/j.gastro.2020.11.011



  7. Pyogenic granuloma of the small bowel treated by double-balloon enteroscopy. Reviewed International journal

    Mizutani Y, Hirooka Y, Watanabe O, Nakamura M, Yamamura T, Ando T, Goto H

    Gastrointestinal endoscopy   Vol. 81 ( 4 ) page: 1023-4   2015.4

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    Authorship:Lead author   Language:English   Publishing type:Research paper (scientific journal)  

    DOI: 10.1016/j.gie.2014.11.005



  8. Identification of cancer restraining CAF

    Mizutani Yasuyuki, Enomoto Atsushi, Takahashi Masahide

    CANCER SCIENCE   Vol. 109   page: 1396-1396   2018.12

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    Authorship:Lead author   Language:English   Publishing type:Research paper (conference, symposium, etc.)  

    Web of Science

  9. [Malignant lymphoma of the pancreas].

    Mizutani Y, Hirooka Y, Kawashima H, Goto H, Ishikawa H

    Nihon rinsho. Japanese journal of clinical medicine   Vol. 73 Suppl 3   page: 381-5   2015.3

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    Authorship:Lead author   Language:English   Publishing type:Research paper (scientific journal)  


  10. Meflin defines mesenchymal stem cells and/or their early progenitors with multilineage differentiation capacity.

    Hara A, Kato K, Ishihara T, Kobayashi H, Asai N, Mii S, Shiraki Y, Miyai Y, Ando R, Mizutani Y, Iida T, Takefuji M, Murohara T, Takahashi M, Enomoto A

    Genes to cells : devoted to molecular & cellular mechanisms   Vol. 26 ( 7 ) page: 495 - 512   2021.7

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher:Genes to Cells  

    Mesenchymal stem cells (MSCs) are the likely precursors of multiple lines of mesenchymal cells. The existence of bona fide MSCs with self-renewal capacity and differentiation potential into all mesenchymal lineages, however, has been unclear because of the lack of MSC-specific marker(s) that are not expressed by the terminally differentiated progeny. Meflin, a glycosylphosphatidylinositol-anchored protein, is an MSC marker candidate that is specifically expressed in rare stromal cells in all tissues. Our previous report showed that Meflin expression becomes down-regulated in bone marrow-derived MSCs cultured on plastic, making it difficult to examine the self-renewal and differentiation of Meflin-positive cells at the single-cell level. Here, we traced the lineage of Meflin-positive cells in postnatal and adult mice, showing that those cells differentiated into white and brown adipocytes, osteocytes, chondrocytes and skeletal myocytes. Interestingly, cells derived from Meflin-positive cells formed clusters of differentiated cells, implying the in situ proliferation of Meflin-positive cells or their lineage-committed progenitors. These results, taken together with previous findings that Meflin expression in cultured MSCs was lost upon their multilineage differentiation, suggest that Meflin is a useful potential marker to localize MSCs and/or their immature progenitors in multiple tissues.

    DOI: 10.1111/gtc.12855



  11. Roles of the Mesenchymal Stromal/Stem Cell Marker Meflin/Islr in Cancer Fibrosis.

    Takahashi M, Kobayashi H, Mizutani Y, Hara A, Iida T, Miyai Y, Asai N, Enomoto A

    Frontiers in cell and developmental biology   Vol. 9   page: 749924   2021

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher:Frontiers in Cell and Developmental Biology  

    Fibroblasts synthesise the extracellular matrix (ECM) such as collagen and elastin, the excessive accumulation of which can lead to fibrosis and organ dysfunction under pathological conditions. Cancer-associated fibroblasts (CAFs) are major constituents of the tumour microenvironment (TME) that accompany the desmoplastic reaction responsible for anti-cancer treatment resistance. Thus, it is important to dissect the roles of CAFs in the TME to develop new therapeutic strategies for refractory cancers. Recent progress in the studies of CAF biology suggests that the functions of CAFs are complicated and that they are composed of functionally distinct populations, including cancer-promoting CAFs (pCAFs) and cancer-restraining CAFs (rCAFs). We recently identified a new cell surface marker for rCAFs in pancreatic and colon cancers, designated as Meflin (mesenchymal stromal cell- and fibroblast-expressing Linx paralogue)/Islr (immunoglobulin super family containing leucine-rich repeat). Based on the distribution of Meflin/Islr-positive cells, we also considered it a specific candidate marker for mesenchymal stroma/stem cells. Meflin/Islr-positive CAFs have been shown to suppress cancer progression by being involved in regulating collagen structures and BMP signalling in the TME. This review describes the function of Meflin/Islr in cancer fibrosis as well as in cardiac and lung fibrosis and its potential in the development of new cancer therapeutics.

    DOI: 10.3389/fcell.2021.749924



  12. Roles of the Mesenchymal Stromal/Stem Cell Marker Meflin in Cardiac Tissue Repair and the Development of Diastolic Dysfunction.

    Hara A, Kobayashi H, Asai N, Saito S, Higuchi T, Kato K, Okumura T, Bando YK, Takefuji M, Mizutani Y, Miyai Y, Saito S, Maruyama S, Maeda K, Ouchi N, Nagasaka A, Miyata T, Mii S, Kioka N, Worthley DL, Murohara T, Takahashi M, Enomoto A

    Circulation research   Vol. 125 ( 4 ) page: 414 - 430   2019.8

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher:Circulation Research  

    Rationale: Myofibroblasts have roles in tissue repair following damage associated with ischemia, aging, and inflammation and also promote fibrosis and tissue stiffening, causing organ dysfunction. One source of myofibroblasts is mesenchymal stromal/stem cells that exist as resident fibroblasts in multiple tissues. We previously identified meflin (mesenchymal stromal cell-and fibroblast-expressing Linx paralogue), a glycosylphosphatidylinositol-Anchored membrane protein, as a specific marker of mesenchymal stromal/stem cells and a regulator of their undifferentiated state. The roles of meflin in the development of heart disease, however, have not been investigated. Objective: We examined the expression of meflin in the heart and its involvement in cardiac repair after ischemia, fibrosis, and the development of heart failure. Methods and Results: We found that meflin has an inhibitory role in myofibroblast differentiation of cultured mesenchymal stromal/stem cells. Meflin expression was downregulated by stimulation with TGF (transforming growth factor)-β, substrate stiffness, hypoxia, and aging. Histological analysis revealed that meflin-positive fibroblastic cells and their lineage cells proliferated in the hearts after acute myocardial infarction and pressure-overload heart failure mouse models. Analysis of meflin knockout mice revealed that meflin is essential for the increase in the number of cells that highly express type I collagen in the heart walls after myocardial infarction induction. When subjected to pressure overload by transverse aortic constriction, meflin knockout mice developed marked cardiac interstitial fibrosis with defective compensation mechanisms. Analysis with atomic force microscopy and hemodynamic catheterization revealed that meflin knockout mice developed stiff failing hearts with diastolic dysfunction. Mechanistically, we found that meflin interacts with bone morphogenetic protein 7, an antifibrotic cytokine that counteracts the action of TGF-β and augments its intracellular signaling. Conclusions: These data suggested that meflin is involved in cardiac tissue repair after injury and has an inhibitory role in myofibroblast differentiation of cardiac fibroblastic cells and the development of cardiac fibrosis.

    DOI: 10.1161/CIRCRESAHA.119.314806



  13. Identification of Meflin as a Potential Marker for Mesenchymal Stromal Cells.

    Maeda K, Enomoto A, Hara A, Asai N, Kobayashi T, Horinouchi A, Maruyama S, Ishikawa Y, Nishiyama T, Kiyoi H, Kato T, Ando K, Weng L, Mii S, Asai M, Mizutani Y, Watanabe O, Hirooka Y, Goto H, Takahashi M

    Scientific reports   Vol. 6   page: 22288   2016.2

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher:Scientific Reports  

    Bone marrow-derived mesenchymal stromal cells (BM-MSCs) in culture are derived from BM stromal cells or skeletal stem cells. Whereas MSCs have been exploited in clinical medicine, the identification of MSC-specific markers has been limited. Here, we report that a cell surface and secreted protein, Meflin, is expressed in cultured MSCs, fibroblasts and pericytes, but not other types of cells including epithelial, endothelial and smooth muscle cells. In vivo, Meflin is expressed by immature osteoblasts and chondroblasts. In addition, Meflin is found on stromal cells distributed throughout the BM, and on pericytes and perivascular cells in multiple organs. Meflin maintains the undifferentiated state of cultured MSCs and is downregulated upon their differentiation, consistent with the observation that Meflin-deficient mice exhibit increased number of osteoblasts and accelerated bone development. In the bone and BM, Meflin is more highly expressed in primitive stromal cells that express platelet-derived growth factor receptor α and Sca-1 than the Sca-1-negative adipo-osteogenic progenitors, which create a niche for hematopoiesis. Those results are consistent with a decrease in the number of clonogenic colony-forming unit-fibroblasts within the BM of Meflin-deficient mice. These preliminary data suggest that Meflin is a potential marker for cultured MSCs and their source cells in vivo.

    DOI: 10.1038/srep22288



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Books 3

  1. 【膵臓の発生・生理・解剖から膵炎・膵癌の病態解明に至る最新の知見】がん抑制性線維芽細胞の本態の理解とその治療応用について

    水谷 泰之(名古屋大学 大学院医学系研究科消化器内科学), 飯田 忠, 石川 卓哉, 大野 栄三郎, 川嶋 啓揮, 藤城 光弘, 榎本 篤( Role: Joint author)

    医学図書出版  2022.8 

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    Total pages:7   Language:Japanese Book type:Textbook, survey, introduction

  2. 胆と膵:膵癌,膵炎の病態解明と新規治療開発にむけた研究の最前線

    水谷泰之( Role: Contributor ,  癌抑制性癌関連線維芽細胞の同定とその臨床応用について)

    医学図書出版  2021.8  ( ISBN:978-4-86517-432-8

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    Language:Japanese Book type:Scholarly book

  3. 膵癌・胆道癌 基礎と臨床の最新研究動向 2015年 03 月号

    水谷泰之( Role: Contributor ,  膵悪性リンパ腫)

    日本臨牀社  2015.3 

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    Language:Japanese Book type:Textbook, survey, introduction

Presentations 3



    2022.5.21  Digestive Disease Week 2022

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    Language:English   Presentation type:Poster presentation  

    Venue:San Diego Convention Center in San Diego   Country:United States  


    Mizutani Y, Enomoto A, Fujishiro M.


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    Language:English   Presentation type:Oral presentation (general)  

    Country:United States  

  3. Meflin-positive cancer-associated fibroblasts inhibit pancreatic carcinogenesis Invited International conference


    UEG  2019.10.23 

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    Language:English   Presentation type:Oral presentation (invited, special)  


Research Project for Joint Research, Competitive Funding, etc. 1

  1. 膵がんのがん関連線維芽細胞多様性の理解に基づく間質標的治療法の開発

    Grant number:21cm0106704h0002  2020.8 - 2021.8

    AMED 次世代がん医療創生研究事業 


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    Authorship:Principal investigator  Grant type:Competitive

    Grant amount:\16000000

KAKENHI (Grants-in-Aid for Scientific Research) 2

  1. 炎症性腸疾患における線維芽細胞の多様性の生物学的意義の解明とその制御

    Grant number:21K15995  2021.4 - 2024.3

    科学研究費助成事業  若手研究

    水谷 泰之

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    Authorship:Principal investigator 

    Grant amount:\4550000 ( Direct Cost: \3500000 、 Indirect Cost:\1050000 )

    ビタミンAはレチノール結合タンパク質(RBP)に結合した形でトランスポーターによって細胞内に取り込まれていることが知られている。本研究では、Meflin陽性線維芽細胞特異的に条件付きビタミンA関連遺伝子欠失マウスを作出し、同細胞がビタミンAの取り込み能を失った場合に個体に与える影響を検証するものである。このために、本年度はビタミンA関連遺伝子のエクソン12の上下流にLoxP配列を組み込んだマウス(ビタミンA関連遺伝子 floxマウス)をゲノム編集の手法で作成した。iGONAD法(経卵管ゲノム編集)により受精卵に導入することで、ビタミンA関連遺伝子 floxマウスの作成を行う。次いで、既に申請者らが作成したMeflin-CreERT2マウスと上記のビタミンA関連遺伝子 floxマウスをかけ合わせることにより、Meflin陽性線維芽細胞特異的にビタミンA関連遺伝子の発現を欠失したマウスを作成し終わった。さらにMeflin-CreERT2 ビタミンA関連遺伝子f/fマウスとActin-Creマウスを掛け合わせてビタミンA関連遺伝子KOマウスを作成した。
    機能解析を進めるためにビタミンA関連遺伝子に特異的な抗体を作成している。またin situ hybridization用のprobeの改良による感度上昇により臨床でビタミンA関連遺伝子の発現をみることが可能であることを確認した。

  2. 膵癌間質の多様性制御に基づく新規治療法の開発

    Grant number:19K17429  2019.4 - 2023.3

    科学研究費助成事業  若手研究

    水谷 泰之

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    Authorship:Principal investigator 

    Grant amount:\4290000 ( Direct Cost: \3300000 、 Indirect Cost:\990000 )

    名古屋大学医学部附属病院にて未治療の切除不能膵がん(遠隔転移例及び局所進行切除不能例)の患者に対して、間質初期化薬として着目したレチノイドとゲムシタビンおよびナブパクリタキセルの併用療法の効果を検証する医師主導治験の第I相部分を開始した( jRCT臨床研究実施計画番号: jRCT2041210056、ClinicalTrials.gov Identifier:NCT05064618)。

Industrial property rights 2

  1. レチノイドとがん治療薬との併用療法が有効ながん患者の選択方法およびレチノイドとがん治療薬との併用医薬


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    Application no:特願2020-110560  Date applied:2021.6

  2. 未分化間葉系幹細胞マーカー及びその用途


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    Application no:PCT/JP2016/071190  Date applied:2015.8


Teaching Experience (On-campus) 4

  1. Special Lecture Tokuron & Tokupro (Translational Research Course)


  2. 消化器救急疾患


  3. 消化器救急疾患


  4. 消化器救急疾患