Updated on 2024/03/22

写真a

 
Yoshimitsu Yura
 
Organization
Nagoya University Hospital Cardiology Assistant professor of hospital
Title
Assistant professor of hospital

Degree 1

  1. PhD ( 2016.9   Nagoya University ) 

Research Interests 2

  1. Clonal Hematopoiesis

  2. Cardiovascular Disease

Research Areas 1

  1. Life Science / Cardiology

Research History 4

  1. Nagoya University Hospital   Department of Cardiovascular Medicine   Assistant professor of hospital

    2021.10

  2. University of Virginia School of Medicine   Department of Cardiovascular Medicine   Assistant Professor

    2021.5 - 2021.9

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    Country:United States

  3. University of Virginia   Cardiovascular Research Center   Research Associate

    2018.4 - 2021.4

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    Country:United States

  4. Boston University School of Medicine   Vascular Biology   Post-doc Researcher

    2017.4 - 2018.3

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    Country:United States

Education 2

  1. Nagoya University

    2012.4 - 2016.3

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    Country: Japan

  2. Nagoya University

    2001.4 - 2007.3

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    Country: Japan

Professional Memberships 2

  1. 日本循環器学会

  2. 日本内科学会

Committee Memberships 1

  1. 日本循環器学会東海支部   若手委員長  

    2021.11   

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    Committee type:Academic society

Awards 3

  1. 日本細胞生物学会論文賞

    2017.5   日本細胞生物学会  

  2. 日本細胞生物学会優秀発表賞

    2015.6   日本細胞生物学会  

  3. 日本薬理学会優秀発表賞

    2015.3   日本薬理学会  

 

Papers 27

  1. Clonal hematopoiesis in clinical and experimental heart failure with preserved ejection fraction Reviewed International coauthorship

    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     2023.9

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

    DOI: 10.1161/CIRCULATIONAHA.123.064170

  2. Therapy-Related Clonal Hematopoiesis: A New Link Between Cancer and Cardiovascular Disease. Invited Reviewed International coauthorship

    Yoshimitsu Yura, Jesse D.Cochran, Kenneth Walsh

        2022.7

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

    DOI: 10.1016/j.hfc.2022.02.010.

  3. Molecular damage in aging Reviewed

    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   Vol. 1 ( 12 ) page: 1096 - 1106   2021.12

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher: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. Reviewed International journal

    Yoshimitsu Yura, Emiri Miura-Yura, Yasufumi Katanasaka, Kyung-Duk Min, Nicholas Chavkin, Ariel H Polizio, Hayato Ogawa, Keita Horitani, Heather Doviak, Megan A Evans, Miho Sano, Ying Wang, Katharina Boroviak, George Philippos, Ana Filipa Domingues, George Vassiliou, Soichi Sano, Kenneth Walsh

    Circulation research   Vol. 129 ( 6 ) page: 684 - 698   2021.9

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    [Figure: see text].

    DOI: 10.1161/CIRCRESAHA.121.319314

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  5. Tet2-mediated clonal hematopoiesis in nonconditioned mice accelerates age-associated cardiac dysfunction. Reviewed International journal

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

    JCI insight   Vol. 5 ( 6 )   2020.3

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

    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. Reviewed International journal

    Yoshimitsu Yura, Soichi Sano, Kenneth Walsh

    JACC. Basic to translational science   Vol. 5 ( 2 ) page: 196 - 207   2020.2

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    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. Reviewed International journal

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

    FASEB journal : official publication of the Federation of American Societies for Experimental Biology   Vol. 33 ( 12 ) page: 14147 - 14158   2019.12

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    Language:Japanese   Publishing type:Research paper (scientific 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.

    DOI: 10.1096/fj.201900786R

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  8. Focused Proteomics Revealed a Novel Rho-kinase Signaling Pathway in the Heart Reviewed

    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   Vol. 41 ( 2 ) page: 105 - 120   2016

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  9. TP53-mediated therapy-related clonal hematopoiesis contributes to doxorubicin-induced cardiomyopathy by augmenting a neutrophil-mediated cytotoxic response. Reviewed International journal

    Soichi Sano, Ying Wang, Hayato Ogawa, Keita Horitani, Miho Sano, Ariel H Polizio, Anupreet Kour, Yoshimitsu Yura, Heather Doviak, Kenneth Walsh

    JCI insight   Vol. 6 ( 13 )   2021.7

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    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. Reviewed International journal

    Ying Wang, Soichi Sano, Hayato Ogawa, Keita Horitani, Megan A Evans, Yoshimitsu Yura, Emiri Miura-Yura, Heather Doviak, Kenneth Walsh

    Cardiovascular research   Vol. 118 ( 6 ) page: 1413 - 1432   2021.6

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    Clonal hematopoiesis (CH) is a phenomenon whereby somatic mutations confer a fitness advantage to hematopoietic stem and progenitor cells (HSPC) and thus facilitate their aberrant clonal expansion. These mutations are carried into progeny leukocytes leading to a situation whereby a substantial fraction of an individual's blood cells originate from the HSPC mutant clone. Although this condition rarely progresses to a hematological malignancy, circulating blood cells bearing the mutation have the potential to affect other organ systems as they infiltrate into tissues under both homeostatic and disease conditions. Epidemiological and clinical studies have revealed that CH is highly prevalent in the elderly and is associated with an increased risk of cardiovascular disease and mortality. Recent experimental studies in murine models have assessed the most commonly mutated "driver" genes associated with CH, and have provided evidence for mechanistic connections between CH and cardiovascular disease. A deeper understanding of the mechanisms by which specific CH mutations promote disease pathogenesis is of importance, as it could pave the way for individualized therapeutic strategies targeting the pathogenic CH gene mutations in the future. Here, we review the epidemiology of CH and the mechanistic work from studies using murine disease models, with a particular focus on the strengths and limitations of these experimental systems. We intend for this review to help investigators select the most appropriate models to study CH in the setting of cardiovascular disease.

    DOI: 10.1093/cvr/cvab215

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  11. Bone Marrow Transplantation Procedures in Mice to Study Clonal Hematopoiesis. Reviewed International journal

    Eunbee Park, Megan A Evans, Heather Doviak, Keita Horitani, Hayato Ogawa, Yoshimitsu Yura, Ying Wang, Soichi Sano, Kenneth Walsh

    Journal of visualized experiments : JoVE   ( 171 )   2021.5

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    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. Reviewed International journal

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

    Cell reports   Vol. 29 ( 10 ) page: 3235 - +   2019.12

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    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.

    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. Reviewed International journal

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

    Circulation   Vol. 140 ( 21 ) page: 1737 - 1752   2019.11

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    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. Reviewed International journal

    Soichi Sano, Ying Wang, Megan A Evans, Yoshimitsu Yura, Miho Sano, Hayato Ogawa, Keita Horitani, Heather Doviak, Kenneth Walsh

    Journal of visualized experiments : JoVE   Vol. 2019 ( 152 )   2019.10

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    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. Reviewed International journal

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

    JACC. Basic to translational science   Vol. 4 ( 6 ) page: 684 - 697   2019.10

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    Janus kinase 2 (valine to phenylalanine at residue 617) (JAK2 V617F ) 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 JAK2 V617F 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 JAK2 V617F mutations 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. Reviewed International journal

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

    Circulation   Vol. 140 ( 6 ) page: 487 - 499   2019.8

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    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. Reviewed International journal

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

    Nature communications   Vol. 8 ( 1 ) page: 33 - 33   2017.6

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    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.Emerging evidence suggests that gut microbiota influences immune function in the brain and may play a role in neurological diseases. Here, the authors offer in vivo evidence from a Drosophila model that supports a role for gut microbiota in modulating the progression of Alzheimer's disease.

    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 Reviewed

    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   Vol. 133 ( 3 ) page: S216 - S216   2017.3

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  19. Identification of Protein Kinase Substrates by the Kinase-Interacting Substrate Screening (KISS) Approach. Reviewed International journal

    Mutsuki Amano, Tomoki Nishioka, Yoshimitsu Yura, Kozo Kaibuchi

    Current protocols in cell biology   Vol. 72   page: 14.16.1-14.16.12 - 14.16.12.   2016.9

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    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. © 2016 by John Wiley & Sons, Inc.

    DOI: 10.1002/cpcb.8

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  20. Focused Proteomics Revealed a Novel Rho-kinase Signaling Pathway in the Heart

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

    Cell Structure and Function   Vol. 41 ( 2 ) page: 105 - 120   2016

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher:Japan Society for Cell Biology  

    <p>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-kinase-mediated substrate. We also found that non-phosphorylatable form of CARP repressed cardiac hypertrophy-related 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.</p>

    DOI: 10.1247/csf.16011

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  21. Kinase-interacting substrate screening is a novel method to identify kinase substrates. Reviewed International journal

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

    The Journal of cell biology   Vol. 209 ( 6 ) page: 895 - 912   2015.6

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

    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

    Web of Science

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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. Reviewed International journal

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

    International journal of cardiology   Vol. 187 ( 1 ) page: 475 - 477   2015.5

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

    DOI: 10.1016/j.ijcard.2015.03.379

    Web of Science

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

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

    Cell Structure and Function   Vol. 40 ( 1 ) page: 1 - 12   2015

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher:Japan Society for Cell Biology  

    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 <i>in vitro</i> and <i>in vivo</i>. 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. In vivo Screening for Substrates of Protein Kinase A Using a Combination of Proteomic Approaches and Pharmacological Modulation of Kinase Activity Reviewed International journal

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

    CELL STRUCTURE AND FUNCTION   Vol. 40 ( 1 ) page: 1 - 12   2015

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

    Web of Science

  25. Phosphoproteomic Analysis Using the WW and FHA Domains as Biological Filters Reviewed International journal

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

    CELL STRUCTURE AND FUNCTION   Vol. 40 ( 2 ) page: 95 - 104   2015

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

    Web of Science

  26. Phosphoproteomic Analysis Using the WW and FHA Domains as Biological Filters

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

    Cell Structure and Function   Vol. 40 ( 2 ) page: 95 - 104   2015

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher:Japan Society for Cell Biology  

    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 Pin1-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. Reviewed International journal

    Mikito Takefuji, Yoshimitsu Yura, Kozo Kaibuchi, Toyoaki Murohara

    Hypertension research : official journal of the Japanese Society of Hypertension   Vol. 36 ( 11 ) page: 930 - 931   2013.11

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

    DOI: 10.1038/hr.2013.101

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Books 1

  1. Therapy Related Clonal hematopoiesis Reviewed International journal

    Yoshimitsu Yura( Role: Contributor ,  Translational Research in Cardio-Oncology)

    Elsevier  2022.7 

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    Total pages:335-528   Responsible for pages:349-359   Language:English Book type:Scholarly book

Presentations 7

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

    Yoshimitsu Yura

    JCS2023 FUKUOKA Annual Scientific Meeting  2023.3.11  Japanese Circulation Society

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

    Venue:Fukuoka   Country:Japan  

  2. Differential regulation of ischemic limb vascularization and tumor growth by endothelial glutaredoxin-1 Invited International conference

    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  2017.11 

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    Language:English   Presentation type:Oral presentation (general)  

  3. Novel substrates of Rho kinase in the heart International conference

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

    MOLECULAR BIOLOGY OF THE CELL  2014.12 

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    Language:English   Presentation type:Poster presentation  

  4. Novel substrates for Rho kinase in the heart International conference

    Yura Yoshimitsu, Amano Mutsuki, Kaibuchi Kozo

    JOURNAL OF PHARMACOLOGICAL SCIENCES  2015.7 

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    Language:English   Presentation type:Oral presentation (general)  

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

    Yoshimitsu Yura

    American Heart Association Scientific Sessions 

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    Language:English   Presentation type:Oral presentation (general)  

    Country:United States  

  6. Focused proteomics revealed a novel Rho-kinase signaling pathway in the heart International conference

    International Vascular Biology Meeting  2016  North American Vascular Biology Organization

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    Language:English   Presentation type:Poster presentation  

    Venue:Boston, Massachusetts   Country:United States  

  7. Effects of aging and sex on redox-regulation of ischemic vascularization International conference

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

    FREE RADICAL BIOLOGY AND MEDICINE  2017.11 

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    Language:English   Presentation type:Oral presentation (general)  

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Research Project for Joint Research, Competitive Funding, etc. 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

    2023.4 - 2026.3

    創発的研究支援事業 

    由良 義充

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    Grant type:Competitive

  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

    2023.4 - 2024.3

    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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    Authorship:Principal investigator  Grant type:Competitive

    Grant amount:\3000000 ( Direct Cost: \3000000 )

  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

    2023.4 - 2024.3

    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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    Authorship:Principal investigator  Grant type:Competitive

  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

    2022.10 - 2024.9

    三菱財団自然科学研究 

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    Authorship:Principal investigator  Grant type:Competitive

    Grant amount:\4000000 ( Direct Cost: \40000000 )

  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

    2022.10 - 2024.9

    第20回榊原記念研究助成 

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    Authorship:Principal investigator  Grant type:Competitive

    Grant amount:\2000000

  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

    2022.10 - 2023.3

    医療分野国際科学技術共同研究開発推進事業 

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    Authorship:Principal investigator  Grant type:Competitive

    Grant amount:\3030000 ( Direct Cost: \2310000 、 Indirect Cost:\693000 )

  7. クローン性造血を介したHFpEF病態の解明

    2022.4 - 2023.3

    堀科学芸術振興財団研究費助成 

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    Authorship:Principal investigator 

  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

    2022.4 - 2023.3

    公益財団法人健康科学財団研究助成 

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    Authorship:Principal investigator  Grant type:Competitive

    Grant amount:\500000 ( Direct Cost: \500000 )

  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

    2022.4 - 2023.3

    中京⻑寿医療研究推進財団医学研究助成 

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    Authorship:Principal investigator  Grant type:Competitive

    Grant amount:\500000 ( Direct Cost: \500000 )

  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

    2021.12

    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

    2021.6 - 2022.5

    Vascular BiologyInnovationに関する研究助成 

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    Authorship:Principal investigator 

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KAKENHI (Grants-in-Aid for Scientific Research) 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

    Grant number: 22K16136  2022.4 - 2024.3

    独立行政法人日本学術振興会  若手研究 

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    Authorship:Principal investigator  Grant type:Competitive

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

 

Teaching Experience (On-campus) 1

  1. 内科 (臨床実習Ⅰ)

    2023