2024/03/22 更新

写真a

ユラ ヨシミツ
由良 義充
Yoshimitsu Yura
所属
医学部附属病院 循環器内科 病院助教
職名
病院助教

学位 1

  1. 博士(医学) ( 2016年9月   名古屋大学 ) 

研究キーワード 2

  1. クローン性造血

  2. 心血管疾患

研究分野 1

  1. ライフサイエンス / 循環器内科学

経歴 4

  1. 名古屋大学医学部附属病院   循環器内科   病院助教

    2021年10月 - 現在

  2. バージニア大学医学部   循環器内科   助教

    2021年5月 - 2021年9月

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    国名:アメリカ合衆国

  3. バージニア大学医学部   心血管研究所   博士研究員

    2018年4月 - 2021年4月

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    国名:アメリカ合衆国

  4. ボストン大学医学部   血管生物学部門   博士研究員

    2017年4月 - 2018年3月

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    国名:アメリカ合衆国

学歴 2

  1. 名古屋大学   医学部   医学系研究科

    2012年4月 - 2016年3月

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    国名: 日本国

  2. 名古屋大学   医学部   医学科

    2001年4月 - 2007年3月

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    国名: 日本国

所属学協会 2

  1. 日本内科学会

  2. 日本循環器学会

委員歴 1

  1. 日本循環器学会東海支部   若手委員長  

    2021年11月 - 現在   

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    団体区分:学協会

受賞 3

  1. 日本細胞生物学会論文賞

    2017年5月   日本細胞生物学会  

  2. 日本細胞生物学会優秀発表賞

    2015年6月   日本細胞生物学会  

  3. 日本薬理学会優秀発表賞

    2015年3月   日本薬理学会  

 

論文 27

  1. Clonal hematopoiesis in clinical and experimental heart failure with preserved ejection fraction 査読有り 国際共著

    Cochran J, Yura Y, Thel MC, Doviak H, Polizio AH, Arai Y, Arai Y, Horitani K, Park E, Chavkin NW, Kour A, Sano S, Mahajan N, Evans M, Huba M, Naya NM, Sun H, Ban Y, Hirschi KK, Toldo S, Abbate A, Druley TE, Ruberg FL, Maurer MS, Ezekowitz JA, Dyck JRB, Walsh K.

    Circulation     2023年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1161/CIRCULATIONAHA.123.064170

  2. Therapy-Related Clonal Hematopoiesis: A New Link Between Cancer and Cardiovascular Disease. 招待有り 査読有り 国際共著

    Yoshimitsu Yura, Jesse D.Cochran, Kenneth Walsh

        2022年7月

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    担当区分:筆頭著者   記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1016/j.hfc.2022.02.010.

  3. Molecular damage in aging 査読有り

    Gladyshev Vadim N., Kritchevsky Stephen B., Clarke Steven G., Cuervo Ana Maria, Fiehn Oliver, de Magalhaes Joao Pedro, Mau Theresa, Maes Michal, Moritz Robert L., Niedernhofer Laura J., Van Schaftingen Emile, Tranah Gregory J., Walsh Kenneth, Yura Yoshimitsu, Zhang Bohan, Cummings Steven R.

    NATURE AGING   1 巻 ( 12 ) 頁: 1096 - 1106   2021年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Nature Aging  

    Cellular metabolism and environmental interactions generate molecular damage affecting all levels of biological organization. Accumulation of this damage over time is thought to have a central role in the aging process. Insufficient attention has been paid to the role of molecular damage in aging-related phenotypes, particularly in humans, in part because of the difficulty in measuring its various forms. Recently, omics approaches have been developed that begin to address this challenge, because they can assess a sizable proportion of age-related damage at the level of small molecules, proteins, RNA, DNA, organelles and cells. This Review describes the concept of molecular damage in aging and discusses its diverse aspects from theoretical models to experimental approaches. Measurement of multiple types of damage enables studies of the role of damage in aging and lays a foundation for testing interventions that reduce the burden of molecular damage, thereby targeting aging.

    DOI: 10.1038/s43587-021-00150-3

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  4. The Cancer Therapy-Related Clonal Hematopoiesis Driver Gene Ppm1d Promotes Inflammation and Non-Ischemic Heart Failure in Mice 査読有り 国際誌

    Yura Y., Miura-Yura E., Katanasaka Y., Min K.D., Chavkin N., Polizio A.H., Ogawa H., Horitani K., Doviak H., Evans M.A., Sano M., Wang Y., Boroviak K., Philippos G., Domingues A.F., Vassiliou G., Sano S., Walsh K.

    Circulation Research   129 巻 ( 6 ) 頁: 684 - 698   2021年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Circulation Research  

    Rationale: Cancer therapy can be associated with short- and long-term cardiac dysfunction. Patients with cancer often exhibit therapy-related clonal hematopoiesis (t-CH), an aggressive form of clonal hematopoiesis that can result from somatic mutations in genes encoding regulators of the DNA-damage response (DDR) pathway. Gain-of-function mutations in exon 6 of the protein phosphatase Mg2+/Mn2+ dependent 1D (PPM1D) gene are the most frequently mutated DNA-damage response gene associated with t-CH. Whether t-CH can contribute to cardiac dysfunction is unknown. Objective: We evaluated the causal and mechanistic relationships between Ppm1d-mediated t-CH and nonischemic heart failure in an experimental system. Methods and Results: To test whether gain-of-function hematopoietic cell mutations in Ppm1d can increase susceptibility to cardiac stress, we evaluated cardiac dysfunction in a mouse model where clonal hematopoiesis-associated mutations in exon 6 of Ppm1d were produced by CRISPR-Cas9 technology. Mice transplanted with hematopoietic stem cells containing the mutated Ppm1d gene exhibited augmented cardiac remodeling following the continuous infusion of Ang II (angiotensin II). Ppm1d-mutant macrophages were impaired in DDR pathway activation and displayed greater DNA damage, higher reactive oxygen species generation, and an augmented proinflammatory profile with elevations in IL (interleukin)-1β and IL-18. The administration of an NLRP3 (NLR family pyrin domain containing 3) inflammasome inhibitor to mice reversed the cardiac phenotype induced by the Ppm1d-mutated hematopoietic stem cells under conditions of Ang II-induced stress. Conclusions: A mouse model of Ppm1d-mediated t-CH was more susceptible to cardiac stress. Mechanistically, disruption of the DDR pathway led to elevations in inflammatory cytokine production, and the NLRP3 inflammasome was shown to be essential for this augmented cardiac stress response. These data indicate that t-CH involving activating mutations in PPM1D can contribute to the cardiac dysfunction observed in cancer survivors, and that anti-inflammatory therapy may have utility in treating this condition.

    DOI: 10.1161/CIRCRESAHA.121.319314

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  5. Tet2-mediated clonal hematopoiesis in nonconditioned mice accelerates age-associated cardiac dysfunction 査読有り 国際誌

    Wang Ying, Sano Soichi, Yura Yoshimitsu, Ke Zhonghe, Sano Miho, Oshima Kosei, Ogawa Hayato, Horitani Keita, Min Kyung-Duk, Miura-Yura Emiri, Kour Anupreet, Evans Megan A., Zuriaga Maria A., Hirschi Karen K., Fuster Jose J., Pietras Eric M., Walsh Kenneth

    JCI INSIGHT   5 巻 ( 6 )   2020年3月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)   出版者・発行元:JCI Insight  

    Clonal hematopoiesis of indeterminate potential is prevalent in elderly individuals and associated with increased risks of all-cause mortality and cardiovascular disease. However, mouse models to study the dynamics of clonal hematopoiesis and its consequences on the cardiovascular system under homeostatic conditions are lacking. We developed a model of clonal hematopoiesis using adoptive transfer of unfractionated ten-eleven translocation 2-mutant (Tet2-mutant) bone marrow cells into nonirradiated mice. Consistent with age-related clonal hematopoiesis observed in humans, these mice displayed a progressive expansion of Tet2-deficient cells in multiple hematopoietic stem and progenitor cell fractions and blood cell lineages. The expansion of the Tet2-mutant fraction was also observed in bone marrow-derived CCR2+ myeloid cell populations within the heart, but there was a negligible impact on the yolk sac-derived CCR2- cardiac-resident macrophage population. Transcriptome profiling revealed an enhanced inflammatory signature in the donor-derived macrophages isolated from the heart. Mice receiving Tet2-deficient bone marrow cells spontaneously developed age-related cardiac dysfunction characterized by greater hypertrophy and fibrosis. Altogether, we show that Tet2-mediated hematopoiesis contributes to cardiac dysfunction in a nonconditioned setting that faithfully models human clonal hematopoiesis in unperturbed bone marrow. Our data support clinical findings that clonal hematopoiesis per se may contribute to diminished health span.

    DOI: 10.1172/jci.insight.135204

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  6. Clonal Hematopoiesis: A New Step Linking Inflammation to Heart Failure 査読有り 国際誌

    Yura Y., Sano S., Walsh K.

    JACC: Basic to Translational Science   5 巻 ( 2 ) 頁: 196 - 207   2020年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:JACC: Basic to Translational Science  

    Heart failure is a common disease with poor prognosis that is associated with cardiac immune cell infiltration and dysregulated cytokine expression. Recently, the clonal expansion of hematopoietic cells with acquired (i.e., nonheritable) DNA mutations, a process referred to as clonal hematopoiesis, has been reported to be associated with cardiovascular diseases including heart failure. Mechanistic studies have shown that leukocytes that harbor these somatic mutations display altered inflammatory characteristics that worsen the phenotypes associated with heart failure in experimental models. In this review, we summarize recent epidemiological and experimental evidence that support the hypothesis that clonal hematopoiesis-mediated immune cell dysfunction contributes to heart failure and cardiovascular disease in general.

    DOI: 10.1016/j.jacbts.2019.08.006

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  7. Endothelial cell-specific redox gene modulation inhibits angiogenesis but promotes B16F0 tumor growth in mice 査読有り 国際誌

    Yura Yoshimitsu, Chong Brian S. H., Johnson Ryan D., Watanabe Yosuke, Tsukahara Yuko, Ferran Beatriz, Murdoch Colin E., Behring Jessica B., McComb Mark E., Costello Catherine E., Janssen-Heininger Yvonne M. W., Cohen Richard A., Bachschmid Markus M., Matsui Reiko

    FASEB JOURNAL   33 巻 ( 12 ) 頁: 14147 - 14158   2019年12月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)   出版者・発行元:FASEB Journal  

    Glutaredoxin-1 (Glrx) is a small cytosolic enzyme that removes S-glutathionylation, glutathione adducts of protein cysteine residues, thus modulating redox signaling and gene transcription. Although Glrx up-regulation prevented endothelial cell (EC) migration and global Glrx transgenic mice had impaired ischemic vascularization, the effects of cell-specific Glrx overexpression remained unknown. Here, we examined the role of EC-specific Glrx up-regulation in distinct models of angiogenesis; namely, hind limb ischemia and tumor angiogenesis. EC-specific Glrx transgenic (EC-Glrx TG) overexpression in mice significantly impaired EC migration in Matrigel implants and hind limb revascularization after femoral artery ligation. Additionally, ECs migrated less into subcutaneously implanted B16F0 melanoma tumors as assessed by decreased staining of EC markers. Despite reduced angiogenesis, EC-Glrx TG mice unexpectedly developed larger tumors compared with control mice. EC-Glrx TG mice showed higher levels of VEGF-A in the tumors, indicating hypoxia, which may stimulate tumor cells to form vascular channels without EC, referred to as vasculogenic mimicry. These data suggest that impaired ischemic vascularization does not necessarily associate with suppression of tumor growth, and that antiangiogenic therapies may be ineffective for melanoma tumors because of their ability to implement vasculogenic mimicry during hypoxia.—Yura, Y., Chong, B. S. H., Johnson, R. D., Watanabe, Y., Tsukahara, Y., Ferran, B., Murdoch, C. E., Behring, J. B., McComb, M. E., Costello, C. E., Janssen-Heininger, Y. M. W., Cohen, R. A., Bachschmid, M. M., Matsui, R. Endothelial cell-specific redox gene modulation inhibits angiogenesis but promotes B16F0 tumor growth in mice. FASEB J. 33, 14147-14158 (2019). www.fasebj.org.

    DOI: 10.1096/fj.201900786R

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  8. Focused Proteomics Revealed a Novel Rho-kinase Signaling Pathway in the Heart 査読有り

    Yura Yoshimitsu, Amano Mutsuki, Takefuji Mikito, Bando Tomohiro, Suzuki Kou, Kato Katsuhiro, Hamaguchi Tomonari, Shohag Md. Hasanuzzaman, Takano Tetsuya, Funahashi Yasuhiro, Nakamuta Shinichi, Kuroda Keisuke, Nishioka Tomoki, Murohara Toyoaki, Kaibuchi Kozo

    CELL STRUCTURE AND FUNCTION   41 巻 ( 2 ) 頁: 105 - 120   2016年

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)  

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  9. TP53-mediated therapy-related clonal hematopoiesis contributes to doxorubicin-induced cardiomyopathy by augmenting a neutrophil-mediated cytotoxic response 査読有り 国際誌

    Sano S., Wang Y., Ogawa H., Horitani K., Sano M., Polizio A.H., Kour A., Yura Y., Doviak H., Walsh K.

    JCI Insight   6 巻 ( 13 )   2021年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:JCI Insight  

    Therapy-related clonal hematopoiesis (t-CH) is often observed in cancer survivors. This form of clonal hematopoiesis typically involves somatic mutations in driver genes that encode components of the DNA damage response and confer hematopoietic stem and progenitor cells (HSPCs) with resistance to the genotoxic stress of the cancer therapy. Here, we established a model of TP53-mediated t-CH through the transfer of Trp53 mutant HSPCs to mice, followed by treatment with a course of the chemotherapeutic agent doxorubicin. These studies revealed that neutrophil infiltration in the heart significantly contributes to doxorubicin-induced cardiac toxicity and that this condition is amplified in the model of Trp53-mediated t-CH. These data suggest that t-CH could contribute to the elevated heart failure risk that occurs in cancer survivors who have been treated with genotoxic agents.

    DOI: 10.1172/jci.insight.146076

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  10. Murine models of clonal hematopoiesis to assess mechanisms of cardiovascular disease. 査読有り 国際誌

    Wang Y, Sano S, Ogawa H, Horitani K, Evans MA, Yura Y, Miura-Yura E, Doviak H, Walsh K

    Cardiovascular research   118 巻 ( 6 ) 頁: 1413 - 1432   2021年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1093/cvr/cvab215

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  11. Bone Marrow Transplantation Procedures in Mice to Study Clonal Hematopoiesis 査読有り 国際誌

    Park E., Evans M.A., Doviak H., Horitani K., Ogawa H., Yura Y., Wang Y., Sano S., Walsh K.

    Journal of visualized experiments : JoVE   ( 171 )   2021年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Journal of visualized experiments : JoVE  

    Clonal hematopoiesis is a prevalent age-associated condition that results from the accumulation of somatic mutations in hematopoietic stem and progenitor cells (HSPCs). Mutations in driver genes, that confer cellular fitness, can lead to the development of expanding HSPC clones that increasingly give rise to progeny leukocytes harboring the somatic mutation. Because clonal hematopoiesis has been associated with heart disease, stroke, and mortality, the development of experimental systems that model these processes is key to understanding the mechanisms that underly this new risk factor. Bone marrow transplantation procedures involving myeloablative conditioning in mice, such as total-body irradiation (TBI), are commonly employed to study the role of immune cells in cardiovascular diseases. However, simultaneous damage to the bone marrow niche and other sites of interest, such as the heart and brain, is unavoidable with these procedures. Thus, our lab has developed two alternative methods to minimize or avoid possible side effects caused by TBI: 1) bone marrow transplantation with irradiation shielding and 2) adoptive BMT to non-conditioned mice. In shielded organs, the local environment is preserved allowing for the analysis of clonal hematopoiesis while the function of resident immune cells is unperturbed. In contrast, the adoptive BMT to non-conditioned mice has the additional advantage that both the local environments of the organs and the hematopoietic niche are preserved. Here, we compare three different hematopoietic cell reconstitution approaches and discuss their strengths and limitations for studies of clonal hematopoiesis in cardiovascular disease.

    DOI: 10.3791/61875

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  12. Phosphorylation of Npas4 by MAPK Regulates Reward-Related Gene Expression and Behaviors 査読有り 国際誌

    Funahashi Yasuhiro, Ariza Anthony, Emi Ryosuke, Xu Yifan, Shan Wei, Suzuki Ko, Kozawa Sachi, Ahammad Rijwan Uddin, Wu Mengya, Takano Tetsuya, Yura Yoshimitsu, Kuroda Keisuke, Nagai Taku, Amano Mutsuki, Yamada Kiyofumi, Kaibuchi Kozo

    CELL REPORTS   29 巻 ( 10 ) 頁: 3235 - +   2019年12月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Cell Reports  

    Dopamine (DA) activates mitogen-activated protein kinase (MAPK) via protein kinase A (PKA)/Rap1 in medium spiny neurons (MSNs) expressing the dopamine D1 receptor (D1R) in the nucleus accumbens (NAc), thereby regulating reward-related behavior. However, how MAPK regulates reward-related learning and memory through gene expression is poorly understood. Here, to identify the relevant transcriptional factors, we perform proteomic analysis using affinity beads coated with cyclic AMP response element binding protein (CREB)-binding protein (CBP), a transcriptional coactivator involved in reward-related behavior. We identify more than 400 CBP-interacting proteins, including Neuronal Per Arnt Sim domain protein 4 (Npas4). We find that MAPK phosphorylates Npas4 downstream of PKA, increasing the Npas4-CBP interaction and the transcriptional activity of Npas4 at the brain-derived neurotrophic factor (BDNF) promoter. The deletion of Npas4 in D1R-expressing MSNs impairs cocaine-induced place preference, which is rescued by Npas4-wild-type (WT), but not by a phospho-deficient Npas4 mutant. These observations suggest that MAPK phosphorylates Npas4 in D1R-MSNs and increases transcriptional activity to enhance reward-related learning and memory. Funahashi et al. isolate and concentrate a transcriptional factor from the mouse striatum using affinity beads coated with CBP and identify more than 400 CBP-interacting proteins, including Npas4. MAPK phosphorylates Npas4 in D1R-MSNs and increases the interaction between Npas4 and CBP, thereby regulating transcriptional activity to enhance reward-related learning and memory.

    DOI: 10.1016/j.celrep.2019.10.116

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  13. Protein Kinase N Promotes Stress-Induced Cardiac Dysfunction Through Phosphorylation of Myocardin-Related Transcription Factor A and Disruption of Its Interaction With Actin 査読有り 国際誌

    Sakaguchi Teruhiro, Takefuji Mikito, Wettschureck Nina, Hamaguchi Tomonari, Amano Mutsuki, Kato Katsuhiro, Tsuda Takuma, Eguchi Shunsuke, Ishihama Sohta, Mori Yu, Yura Yoshimitsu, Yoshida Tatsuya, Unno Kazumasa, Okumura Takahiro, Ishii Hideki, Shimizu Yuuki, Bando Yasuko K., Ohashi Koji, Ouchi Noriyuki, Enomoto Atsushi, Offermanns Stefan, Kaibuchi Kozo, Murohara Toyoaki

    CIRCULATION   140 巻 ( 21 ) 頁: 1737 - 1752   2019年11月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Circulation  

    Background: Heart failure is a complex syndrome that results from structural or functional impairment of ventricular filling or blood ejection. Protein phosphorylation is a major and essential intracellular mechanism that mediates various cellular processes in cardiomyocytes in response to extracellular and intracellular signals. The RHOA-associated protein kinase (ROCK/Rho-kinase), an effector regulated by the small GTPase RHOA, causes pathological phosphorylation of proteins, resulting in cardiovascular diseases. RHOA also activates protein kinase N (PKN); however, the role of PKN in cardiovascular diseases remains unclear. Methods: To explore the role of PKNs in heart failure, we generated tamoxifen-inducible, cardiomyocyte-specific PKN1- and PKN2-knockout mice by intercrossing the αMHC-CreERT2 line with Pkn1flox/flox and Pkn2flox/flox mice and applied a mouse model of transverse aortic constriction- and angiotensin II-induced heart failure. To identify a novel substrate of PKNs, we incubated GST-tagged myocardin-related transcription factor A (MRTFA) with recombinant GST-PKN-catalytic domain or GST-ROCK-catalytic domain in the presence of radiolabeled ATP and detected radioactive GST-MRTFA as phosphorylated MRTFA. Results: We demonstrated that RHOA activates 2 members of the PKN family of proteins, PKN1 and PKN2, in cardiomyocytes of mice with cardiac dysfunction. Cardiomyocyte-specific deletion of the genes encoding Pkn1 and Pkn2 (cmc-PKN1/2 DKO) did not affect basal heart function but protected mice from pressure overload- and angiotensin II-induced cardiac dysfunction. Furthermore, we identified MRTFA as a novel substrate of PKN1 and PKN2 and found that MRTFA phosphorylation by PKN was considerably more effective than that by ROCK in vitro. We confirmed that endogenous MRTFA phosphorylation in the heart was induced by pressure overload- and angiotensin II-induced cardiac dysfunction in wild-type mice, whereas cmc-PKN1/2 DKO mice suppressed transverse aortic constriction- and angiotensin II-induced phosphorylation of MRTFA. Although RHOA-mediated actin polymerization accelerated MRTFA-induced gene transcription, PKN1 and PKN2 inhibited the interaction of MRTFA with globular actin by phosphorylating MRTFA, causing increased serum response factor-mediated expression of cardiac hypertrophy- and fibrosis-associated genes. Conclusions: Our results indicate that PKN1 and PKN2 activation causes cardiac dysfunction and is involved in the transition to heart failure, thus providing unique targets for therapeutic intervention for heart failure.

    DOI: 10.1161/CIRCULATIONAHA.119.041019

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  14. Lentiviral CRISPR/Cas9-mediated genome editing for the study of hematopoietic cells in disease models 査読有り 国際誌

    Sano S., Wang Y., Evans M.A., Yura Y., Sano M., Ogawa H., Horitani K., Doviak H., Walsh K.

    Journal of Visualized Experiments   2019 巻 ( 152 )   2019年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Journal of Visualized Experiments  

    Manipulating genes in hematopoietic stem cells using conventional transgenesis approaches can be time-consuming, expensive, and challenging. Benefiting from advances in genome editing technology and lentivirus-mediated transgene delivery systems, an efficient and economical method is described here that establishes mice in which genes are manipulated specifically in hematopoietic stem cells. Lentiviruses are used to transduce Cas9-expressing lineage-negative bone marrow cells with a guide RNA (gRNA) targeting specific genes and a red fluorescence reporter gene (RFP), then these cells are transplanted into lethally-irradiated C57BL/6 mice. Mice transplanted with lentivirus expressing non-targeting gRNA are used as controls. Engraftment of transduced hematopoietic stem cells are evaluated by flow cytometric analysis of RFP-positive leukocytes of peripheral blood. Using this method, ~90% transduction of myeloid cells and ~70% of lymphoid cells at 4 weeks after transplantation can be achieved. Genomic DNA is isolated from RFP-positive blood cells, and portions of the targeted site DNA are amplified by PCR to validate the genome editing. This protocol provides a high-throughput evaluation of hematopoiesis-regulatory genes and can be extended to a variety of mouse disease models with hematopoietic cell involvement.

    DOI: 10.3791/59977

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  15. JAK2(V617F)-Mediated Clonal Hematopoiesis Accelerates Pathological Remodeling in Murine Heart Failure 査読有り 国際誌

    Sano Soichi, Wang Ying, Yura Yoshimitsu, Sano Miho, Oshima Kosei, Yang Yue, Katanasaka Yasufumi, Min Kyung-Duk, Matsuura Shinobu, Ravid Katya, Mohi Golam, Walsh Kenneth

    JACC-BASIC TO TRANSLATIONAL SCIENCE   4 巻 ( 6 ) 頁: 684 - 697   2019年10月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)   出版者・発行元:JACC: Basic to Translational Science  

    Janus kinase 2 (valine to phenylalanine at residue 617) (JAK2V617F) mutations lead to myeloproliferative neoplasms associated with elevated myeloid, erythroid, and megakaryocytic cells. Alternatively these same mutations can lead to the condition of clonal hematopoiesis with no impact on blood cell counts. Here, a model of myeloid-restricted JAK2V617F expression from lineage-negative bone marrow cells was developed and evaluated. This model displayed greater cardiac inflammation and dysfunction following permanent left anterior descending artery ligation and transverse aortic constriction. These data suggest that JAK2V617Fmutations arising in myeloid progenitor cells may contribute to cardiovascular disease by promoting the proinflammatory properties of circulating myeloid cells.

    DOI: 10.1016/j.jacbts.2019.05.013

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  16. Wnt5a-Mediated Neutrophil Recruitment Has an Obligatory Role in Pressure Overload-Induced Cardiac Dysfunction 査読有り 国際誌

    Wang Ying, Sano Soichi, Oshima Kosei, Sano Miho, Watanabe Yosuke, Katanasaka Yasufumi, Yura Yoshimitsu, Jung Changhee, Anzai Atsushi, Swirski Filip K., Gokce Noyan, Walsh Kenneth

    CIRCULATION   140 巻 ( 6 ) 頁: 487 - 499   2019年8月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Circulation  

    Background: Although the complex roles of macrophages in myocardial injury are widely appreciated, the function of neutrophils in nonischemic cardiac pathology has received relatively little attention. Methods: To examine the regulation and function of neutrophils in pressure overload-induced cardiac hypertrophy, mice underwent treatment with Ly6G antibody to deplete neutrophils and then were subjected to transverse aortic constriction. Results: Neutrophil depletion diminished transverse aortic constriction-induced hypertrophy and inflammation and preserved cardiac function. Myeloid deficiency of Wnt5a, a noncanonical Wnt, suppressed neutrophil infiltration to the hearts of transverse aortic constriction-treated mice and produced a phenotype that was similar to the neutropenic conditions. Conversely, mice overexpressing Wnt5a in myeloid cells displayed greater hypertrophic growth, inflammation, and cardiac dysfunction. Neutrophil depletion reversed the Wnt5a overexpression-induced cardiac pathology and eliminated differences in cardiac parameters between wild-type and myeloid-specific Wnt5a transgenic mice. Conclusions: These findings reveal that Wnt5a-regulated neutrophil infiltration has a critical role in pressure overload-induced heart failure.

    DOI: 10.1161/CIRCULATIONAHA.118.038820

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  17. Discovery of long-range inhibitory signaling to ensure single axon formation 査読有り 国際誌

    Takano Tetsuya, Wu Mengya, Nakamuta Shinichi, Naoki Honda, Ishizawa Naruki, Namba Takashi, Watanabe Takashi, Xu Chundi, Hamaguchi Tomonari, Yura Yoshimitsu, Amano Mutsuki, Hahn Klaus M., Kaibuchi Kozo

    NATURE COMMUNICATIONS   8 巻 ( 1 ) 頁: 33 - 33   2017年6月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Nature Communications  

    A long-standing question in neurodevelopment is how neurons develop a single axon and multiple dendrites from common immature neurites. Long-range inhibitory signaling from the growing axon is hypothesized to prevent outgrowth of other immature neurites and to differentiate them into dendrites, but the existence and nature of this inhibitory signaling remains unknown. Here, we demonstrate that axonal growth triggered by neurotrophin-3 remotely inhibits neurite outgrowth through long-range Ca2+ waves, which are delivered from the growing axon to the cell body. These Ca2+ waves increase RhoA activity in the cell body through calcium/calmodulin-dependent protein kinase I. Optogenetic control of Rho-kinase combined with computational modeling reveals that active Rho-kinase diffuses to growing other immature neurites and inhibits their outgrowth. Mechanistically, calmodulin-dependent protein kinase I phosphorylates a RhoA-specific GEF, GEF-H1, whose phosphorylation enhances its GEF activity. Thus, our results reveal that long-range inhibitory signaling mediated by Ca2+ wave is responsible for neuronal polarization.

    DOI: 10.1038/s41467-017-00044-2

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  18. Dopamine-induced phosphorylation of NPAS4 through MAPK regulates reward-related learning and memory 査読有り

    Yasuhiro Funahashi, Ariza Anthony, Wei Shan, Kozawa Sachi, Okuda Keiichiro, Suzuki Ko, Takano Tetsuya, Yura Yoshimitsu, Kuroda Keisuke, Nagai Taku, Kaibuchi Kozo

    JOURNAL OF PHARMACOLOGICAL SCIENCES   133 巻 ( 3 ) 頁: S216 - S216   2017年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Web of Science

  19. Identification of protein kinase substrates by the kinase-interacting substrate screening (KISS) approach 査読有り 国際誌

    Amano M., Nishioka T., Yura Y., Kaibuchi K.

    Current Protocols in Cell Biology   72 巻   頁: 14.16.1-14.16.12 - 14.16.12.   2016年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Current Protocols in Cell Biology  

    Identifying the substrates of protein kinases to understand their modes of action has been undertaken by various approaches and remains an ongoing challenge. Phosphoproteomic technologies have accelerated the accumulation of data concerning protein phosphorylation and have uncovered vast numbers of phosphorylation sites in vivo. In this unit, a novel in vitro screening approach for protein kinase substrates is presented, based on protein-protein interaction and mass spectrometry-based phosphoproteomic technology.

    DOI: 10.1002/cpcb.8

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  20. Focused proteomics revealed a novel Rho-kinase signaling pathway in the heart

    Yura Y., Amano M., Takefuji M., Bando T., Suzuki K., Kato K., Hamaguchi T., Shohag M.H., Takano T., Funahashi Y., Nakamuta S., Kuroda K., Nishioka T., Murohara T., Kaibuchi K.

    Cell Structure and Function   41 巻 ( 2 ) 頁: 105 - 120   2016年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:日本細胞生物学会  

    Protein phosphorylation plays an important role in the physiological regulation of cardiac function. Myocardial contraction and pathogenesis of cardiac diseases have been reported to be associated with adaptive or maladaptive protein phosphorylation; however, phosphorylation signaling in the heart is not fully elucidated. We recently developed a novel kinase-interacting substrate screening (KISS) method for exhaustive screening of protein kinase substrates, using mass spectrometry and affinity chromatography. First, we examined protein phosphorylation by extracellular signal-regulated kinase (ERK) and protein kinase A (PKA), which has been relatively well studied in cardiomyocytes. The KISS method showed that ERK and PKA mediated the phosphorylation of known cardiac-substrates of each kinase such as Rps6ka1 and cTnI, respectively. Using this method, we found about 330 proteins as Rho-kinase-mediated substrates, whose substrate in cardiomyocytes is unknown. Among them, CARP/Ankrd1, a muscle ankyrin repeat protein, was confirmed as a novel Rho-kinasemediated substrate. We also found that non-phosphorylatable form of CARP repressed cardiac hypertrophyrelated gene Myosin light chain-2v (MLC-2v) promoter activity, and decreased cell size of heart derived H9c2 myoblasts more efficiently than wild type-CARP. Thus, focused proteomics enable us to reveal a novel signaling pathway in the heart.

    DOI: 10.1247/csf.16011

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  21. Kinase-interacting substrate screening is a novel method to identify kinase substrates 査読有り 国際誌

    Amano Mutsuki, Hamaguchi Tomonari, Shohag Md. Hasanuzzaman, Kozawa Kei, Kato Katsuhiro, Zhang Xinjian, Yura Yoshimitsu, Matsuura Yoshiharu, Kataoka Chikako, Nishioka Tomoki, Kaibuchi Kozo

    JOURNAL OF CELL BIOLOGY   209 巻 ( 6 ) 頁: 895 - 912   2015年6月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Journal of Cell Biology  

    Protein kinases play pivotal roles in numerous cellular functions; however, the specific substrates of each protein kinase have not been fully elucidated. We have developed a novel method called kinase-interacting substrate screening (KISS). Using this method, 356 phosphorylation sites of 140 proteins were identified as candidate substrates for Rho-associated kinase (Rho-kinase/ROCK2), including known substrates. The KISS method was also applied to additional kinases, including PKA, MAPK1, CDK5, CaMK1, PAK7, PKN, LYN, and FYN, and a lot of candidate substrates and their phosphorylation sites were determined, most of which have not been reported previously. Among the candidate substrates for Rho-kinase, several functional clusters were identified, including the polarity-associated proteins, such as Scrib. We found that Scrib plays a crucial role in the regulation of subcellular contractility by assembling into a ternary complex with Rho-kinase and Shroom2 in a phosphorylation-dependent manner. We propose that the KISS method is a comprehensive and useful substrate screen for various kinases.

    DOI: 10.1083/jcb.201412008

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  22. New-onset atrial fibrillation may be a more important predictor of cardiac mortality in acute myocardial infarction patients than preexisting atrial fibrillation 査読有り 国際誌

    Morishima Itsuro, Tomomatsu Toshiro, Okumura Kenji, Sone Takahito, Tsuboi Hideyuki, Morita Yasuhiro, Inoue Yosuke, Yoshida Ruka, Yura Yoshimitsu, Murohara Toyoaki

    INTERNATIONAL JOURNAL OF CARDIOLOGY   187 巻 ( 1 ) 頁: 475 - 477   2015年5月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)   出版者・発行元:International Journal of Cardiology  

    DOI: 10.1016/j.ijcard.2015.03.379

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  23. In vivo Screening for Substrates of Protein Kinase A Using a Combination of Proteomic Approaches and Pharmacological Modulation of Kinase Activity

    Hamaguchi T., Nakamuta S., Funahashi Y., Takano T., Nishioka T., Shohag M.H., Yura Y., Kaibuchi K., Amano M.

    Cell Structure and Function   40 巻 ( 1 ) 頁: 1 - 12   2015年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:日本細胞生物学会  

    Protein kinase A (PKA) is a serine/threonine kinase whose activity depends on the levels of cyclic AMP (cAMP). PKA plays essential roles in numerous cell types such as myocytes and neurons. Numerous substrate screens have been attempted to clarify the entire scope of the PKA signaling cascade, but it is still underway. Here, we performed a comprehensive screen that consisted of immunoprecipitation and mass spectrometry, with a focus on the identification of PKA substrates. The lysate of HeLa cells treated with Forskolin (FSK)/3-isobutyl methyl xanthine (IBMX) and/or H-89 was subjected to immunoprecipitation using anti-phospho-PKA substrate antibody. The identity of the phosophoproteins and phosphorylation sites in the precipitants was determined using liquid chromatography tandem mass spectrometry (LC/MS/MS). We obtained 112 proteins as candidate substrates and 65 candidate sites overall. Among the candidate substrates, Rho-kinase/ ROCK2 was confirmed to be a novel substrate of PKA both in vitro and in vivo. In addition to Rho-kinase, we found more than a hundred of novel candidate substrates of PKA using this screen, and these discoveries provide us with new insights into PKA signaling.

    DOI: 10.1247/csf.14014

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  24. Phosphoproteomic Analysis Using the WW and FHA Domains as Biological Filters 査読有り 国際誌

    Shohag Md. Hasanuzzaman, Nishioka Tomoki, Ahammad Rijwan Uddin, Nakamuta Shinichi, Yura Yoshimitsu, Hamaguchi Tomonari, Kaibuchi Kozo, Amano Mutsuki

    CELL STRUCTURE AND FUNCTION   40 巻 ( 2 ) 頁: 95 - 104   2015年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Web of Science

  25. In vivo Screening for Substrates of Protein Kinase A Using a Combination of Proteomic Approaches and Pharmacological Modulation of Kinase Activity 査読有り 国際誌

    Hamaguchi Tomonari, Nakamuta Shinichi, Funahashi Yasuhiro, Takano Tetsuya, Nishioka Tomoki, Shohag Md. Hasanuzzaman, Yura Yoshimitsu, Kaibuchi Kozo, Amano Mutsuki

    CELL STRUCTURE AND FUNCTION   40 巻 ( 1 ) 頁: 1 - 12   2015年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Web of Science

  26. Phosphoproteomic analysis using the WW and FHA domains as biological filters

    Shohag M.H., Nishioka T., Ahammad R.U., Nakamuta S., Yura Y., Hamaguchi T., Kaibuchi K., Amano M.

    Cell Structure and Function   40 巻 ( 2 ) 頁: 95 - 104   2015年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:日本細胞生物学会  

    Protein phosphorylation plays a key role in regulating nearly all intracellular biological events. However, poorly developed phospho-specific antibodies and low phosphoprotein abundance make it difficult to study phosphoproteins. Cellular protein phosphorylation data have been obtained using phosphoproteomic approaches, but the detection of low-abundance or fast-cycling phosphorylation sites remains a challenge. Enrichment of phosphoproteins together with phosphopeptides may greatly enhance the spectrum of low-abundance but biologically important phosphoproteins. Previously, we used 14-3-3ζ to selectively enrich for HeLa cell lysate phosphoproteins. However, because 14-3-3 does not isolate phosphoproteins lacking the 14-3-3-binding motif, we looked for other domains that could complementarily enrich for phosphoproteins. We here assessed and characterized the phosphoprotein binding domains Pinl-WW, CHEK2-FHA, and DLG1-GK Using a strategy based on affinity chromatography, phosphoproteins were collected from the lysates of HeLa cells treated with phosphatase inhibitor or cAMP activator. We identified different subsets of phosphoproteins associated with WW or FHA after calyculin A, okadaic acid, or forskolin treatment. Our Kinase-Oriented Substrate Screening (KiOSS) method, which used phosphoprotein-binding domains, showed that WW and FHA are applicable and useful for the identification of novel phospho-substrates for kinases and can therefore be used as biological filters for comprehensive phosphoproteome analysis.

    DOI: 10.1247/csf.15004

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  27. RhoGEF-mediated vasoconstriction in hypertension 査読有り 国際誌

    Takefuji Mikito, Yura Yoshimitsu, Kaibuchi Kozo, Murohara Toyoaki

    HYPERTENSION RESEARCH   36 巻 ( 11 ) 頁: 930 - 931   2013年11月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Hypertension Research  

    DOI: 10.1038/hr.2013.101

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▼全件表示

書籍等出版物 1

  1. Therapy Related Clonal hematopoiesis 査読有り 国際共著

    Yoshimitsu Yura( 担当: 分担執筆 ,  範囲: Translational Research in Cardio-Oncology)

    Elsevier  2022年7月 

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    総ページ数:335-528   担当ページ:349-359   記述言語:英語 著書種別:学術書

講演・口頭発表等 7

  1. Clonal Hematopoiesis in Patients with Cancer -A new potential link between Cancer and Cardiovascular disease 招待有り

    Yoshimitsu Yura

    JCS2023 FUKUOKA Annual Scientific Meeting  2023年3月11日  Japanese Circulation Society

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    記述言語:英語   会議種別:口頭発表(招待・特別)  

    開催地:Fukuoka   国名:日本国  

  2. Differential regulation of ischemic limb vascularization and tumor growth by endothelial glutaredoxin-1 招待有り 国際会議

    Yura Yoshimitsu, Johnson Ryan, Watanabe Yosuke, Tsukahara Yuko, Ferran Beatriz Perez, Murdoch Colin, van der Velden Jos, Bachschmid Markus Michael, Heininger Yvonne Janssen, Matsui Reiko

    FREE RADICAL BIOLOGY AND MEDICINE  2017年11月 

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    記述言語:英語   会議種別:口頭発表(一般)  

  3. Novel substrates of Rho kinase in the heart 国際会議

    Yura Y., Bando T., Amano M., Kaibuchi K.

    MOLECULAR BIOLOGY OF THE CELL  2014年12月 

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    記述言語:英語   会議種別:ポスター発表  

  4. Novel substrates for Rho kinase in the heart 国際会議

    Yura Yoshimitsu, Amano Mutsuki, Kaibuchi Kozo

    JOURNAL OF PHARMACOLOGICAL SCIENCES  2015年7月 

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    記述言語:英語   会議種別:口頭発表(一般)  

  5. The Therapy-related Clonal Hematopoiesis Driver Gene Ppm1d Promotes Inflammation and Non-ischemic Heart Failure in a Murine Model 国際会議

    Yoshimitsu Yura

    American Heart Association Scientific Sessions 

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    記述言語:英語   会議種別:口頭発表(一般)  

    国名:アメリカ合衆国  

  6. Focused proteomics revealed a novel Rho-kinase signaling pathway in the heart 国際会議

    International Vascular Biology Meeting  2016年  North American Vascular Biology Organization

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    記述言語:英語   会議種別:ポスター発表  

    開催地:Boston, Massachusetts   国名:アメリカ合衆国  

  7. Effects of aging and sex on redox-regulation of ischemic vascularization 国際会議

    Perez Beatriz Ferran, Tsukahara Yuko, Yura Yoshimitsu, Bachschmid Markus M., Matsui Reiko

    FREE RADICAL BIOLOGY AND MEDICINE  2017年11月 

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    記述言語:英語   会議種別:口頭発表(一般)  

▼全件表示

共同研究・競争的資金等の研究課題 11

  1. クローン性造血を介した加齢性心血管病の病態解明

    2023年4月 - 2026年3月

    創発的研究支援事業 

    由良 義充

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    資金種別:競争的資金

  2. クローン性造血に着目した心収縮能が保たれた心不全の病態解明

    2023年4月 - 2024年3月

    公益財団法人持田記念医学薬学振興財団研究助成 

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    担当区分:研究代表者  資金種別:競争的資金

    配分額:3000000円 ( 直接経費:3000000円 )

  3. 造血幹細胞における体細胞変異が加齢性心臓病に与える影響の解明

    2023年4月 - 2024年3月

    公益財団法人鈴木謙三記念医科学応用研究財団 調査研究助成 

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    担当区分:研究代表者  資金種別:競争的資金

  4. クローン性造血を介した心収縮能の保たれた心不全病態の解明

    2022年10月 - 2024年9月

    三菱財団自然科学研究 

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    担当区分:研究代表者  資金種別:競争的資金

    配分額:4000000円 ( 直接経費:40000000円 )

  5. クローン性造血による新型コロナウイルス感染症に伴う心筋炎発症メカニズムの解明

    2022年10月 - 2024年9月

    第20回榊原記念研究助成 

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    担当区分:研究代表者  資金種別:競争的資金

    配分額:2000000円

  6. DNA傷害応答遺伝子におけるクローン性造血が心血管疾患に与える影響の解明

    2022年10月 - 2023年3月

    医療分野国際科学技術共同研究開発推進事業 

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    担当区分:研究代表者  資金種別:競争的資金

    配分額:3030000円 ( 直接経費:2310000円 、 間接経費:693000円 )

  7. クローン性造血を介したHFpEF病態の解明

    2022年4月 - 2023年3月

    堀科学芸術振興財団研究費助成 

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    担当区分:研究代表者 

  8. 心収縮能が保たれた心不全の病態にクローン性造血が与える影響の検討

    2022年4月 - 2023年3月

    公益財団法人健康科学財団研究助成 

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    担当区分:研究代表者  資金種別:競争的資金

    配分額:500000円 ( 直接経費:500000円 )

  9. 高齢者に高頻度に認める心収縮能が保たれた心不全の病態にクローン性造血が与える影響の検討

    2022年4月 - 2023年3月

    中京⻑寿医療研究推進財団医学研究助成 

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    担当区分:研究代表者  資金種別:競争的資金

    配分額:500000円 ( 直接経費:500000円 )

  10. クローン性造血に着目した小児がん治療後の心不全発症のメカニズムの解明

    2021年12月 - 現在

    未成年心臓血管病の学究等に対する奨励金 

  11. クローン性造血が血管新生に与える影響の検討

    2021年6月 - 2022年5月

    Vascular BiologyInnovationに関する研究助成 

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    担当区分:研究代表者 

▼全件表示

科研費 1

  1. クローン性造血がHFpEF病態を修飾するメカニズムの解明

    研究課題/研究課題番号: 22K16136  2022年4月 - 2024年3月

    独立行政法人日本学術振興会  若手研究 

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    担当区分:研究代表者  資金種別:競争的資金

    配分額:4550000円 ( 直接経費:3500000円 、 間接経費:1050000円 )

 

担当経験のある科目 (本学) 1

  1. 内科 (臨床実習Ⅰ)

    2023