Updated on 2023/03/01

写真a

 
NAKAMURA Tomoko
 
Organization
Nagoya University Hospital Maternity and Perinatal Care Center Associate professor
Graduate School
Graduate School of Medicine
Title
Associate professor

Degree 1

  1. 博士（医学） （ 2014.10   名古屋大学 ） 

To the head of Degree.▲
 

Papers 29

  1. Functional Lactotrophs in Induced Adenohypophysis Differentiated From Human iPS Cells

    Miyake Natsuki, Nagai Takashi, Suga Hidetaka, Osuka Satoko, Kasai Takatoshi, Sakakibara Mayu, Soen Mika, Ozaki Hajime, Miwata Tsutomu, Asano Tomoyoshi, Kano Mayuko, Muraoka Ayako, Nakanishi Natsuki, Nakamura Tomoko, Goto Maki, Yasuda Yoshinori, Kawaguchi Yohei, Miyata Takashi, Kobayashi Tomoko, Sugiyama Mariko, Onoue Takeshi, Hagiwara Daisuke, Iwama Shintaro, Iwase Akira, Inoshita Naoko, Arima Hiroshi, Kajiyama Hiroaki

    ENDOCRINOLOGY   Vol. 163 ( 3 )   2022.3

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    Language：Japanese   Publisher：Endocrinology (United States)  

    Prolactin (PRL), a hormone involved in lactation, is mainly produced and secreted by the lactotrophs of the anterior pituitary (AP) gland. We previously reported a method to generate functional adrenocorticotropic hormone-producing cells by differentiating the AP and hypothalamus simultaneously from human induced pluripotent stem cells (iPSCs). However, PRL-producing cells in the induced AP have not been investigated. Here, we confirmed the presence of PRL-producing cells and evaluated their endocrine functions. We differentiated pituitary cells from human iPSCs using serum-free floating culture of embryoid-like aggregates with quick reaggregation (SFEB-q) method and evaluated the appearance and function of PRL-producing cells. Secretion of PRL from the differentiated aggregates was confirmed, which increased with further culture. Fluorescence immunostaining and immunoelectron microscopy revealed PRL-producing cells and PRL-positive secretory granules, respectively. PRL secretion was promoted by various prolactin secretagogues such as thyrotropin-releasing hormone, vasoactive intestinal peptide, and prolactin-releasing peptide, and inhibited by bromocriptine. Moreover, the presence of tyrosine hydroxylase-positive dopaminergic nerves in the hypothalamic tissue area around the center of the aggregates connecting to PRL-producing cells indicated the possibility of recapitulating PRL regulatory mechanisms through the hypothalamus. In conclusion, we generated pituitary lactotrophs from human iPSCs; these displayed similar secretory responsiveness as human pituitary cells in vivo. In the future, this is expected to be used as a model of human PRL-producing cells for various studies, such as drug discovery, prediction of side effects, and elucidation of tumorigenic mechanisms using disease-specific iPSCs. Furthermore, it may help to develop regenerative medicine for the pituitary gland.

    DOI： 10.1210/endocr/bqac004

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  2. Tamoxifen Activates Dormant Primordial Follicles in Mouse Ovaries

    Wei Wei, Komatsu Kouji, Osuka Satoko, Murase Tomohiko, Bayasula Bayasula, Nakanishi Natsuki, Nakamura Tomoko, Goto Maki, Iwase Akira, Masubuchi Satoru, Kajiyama Hiroaki

    REPRODUCTIVE SCIENCES     2022.2

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    Language：Japanese   Publisher：Reproductive Sciences  

    Our previous study found that 17β-estradiol (E2) suppresses primordial follicle activation and growth in cultured mouse ovaries. In this study, we administered tamoxifen, an estrogen receptor antagonist, into the abdominal cavity of mice to clarify the relationship between primordial follicle activation and the physiological concentration of E2 in mouse ovaries. The results showed that tamoxifen promoted primordial follicle activation. Administration of tamoxifen promoted degradation of the extracellular matrix surrounding primordial follicles in the ovaries. Furthermore, tamoxifen decreased the expression of stefin A, an inhibitor of cathepsins that digest some proteins and extracellular matrix, in the ovaries. Mechanical stress produced by the extracellular matrix reportedly suppresses the activation of primordial follicles. The collective results show that tamoxifen can promote primordial follicle activation through the degradation of the extracellular matrix surrounding primordial follicles. Our results indicate that E2 suppresses primordial follicle activation in vivo and that tamoxifen may be useful as a therapeutic agent against infertility. Graphical abstract: [Figure not available: see fulltext.]

    DOI： 10.1007/s43032-022-00896-0

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  3. Impact of perioperative use of GnRH agonist or dienogest on ovarian reserve after cystectomy for endometriomas: a randomized controlled trial

    Muraoka Ayako, Osuka Satoko, Yabuki Atsushi, Bayasula, Yoshihara Masato, Tanaka Hideaki, Sonehara Reina, Miyake Natsuki, Murakami Mayuko, Yoshita Sayako, Nakanishi Natsuki, Nakamura Tomoko, Goto Maki, Iwase Akira, Kajiyama Hiroaki

    REPRODUCTIVE BIOLOGY AND ENDOCRINOLOGY   Vol. 19 ( 1 ) page： 179   2021.12

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    Language：Japanese   Publisher：Reproductive Biology and Endocrinology  

    Background: Ovarian endometrioma is a common gynecological disease that is often treated with surgery or hormonal treatment. Ovarian cystectomy, a surgical procedure for ovarian endometrioma, can result in impaired ovarian reserve. Methods: We conducted a randomized controlled trial to evaluate the efficacy of hormonal treatment [gonadotropin-releasing hormone agonist (GnRHa) or dienogest (DNG)] for preserving ovarian reserve after cystectomy for ovarian endometrioma. The primary endpoint was the level of serum Anti-Müllerian hormone (AMH) as a marker of ovarian reserve. Results: Before and after laparoscopic surgery, 22 patients in the GnRHa group and 27 patients in the DNG group were administered hormonal treatment for a total of 4 months. After 1-year follow-up, >60% of the patients in the DNG group retained over 70% of their pretreatment AMH levels, whereas no patient in the GnRHa group retained their AMH levels after cystectomy (P < 0.01). Interleukin-6 (IL-6) is a key cytokine involved in inflammation. Compared with the GnRHa group, patients in the DNG group had lower IL-6 levels at the end of treatment. Conclusions: Our data revealed that DNG is more effective than GnRHa in preserving ovarian reserve after cystectomy of ovarian endometrioma. This is achieved through the reduction of the inflammatory response during the perioperative period and other endometriosis-related inflammatory reactions. Trial registration: The registration number of this trial is UMIN-CTR, UMIN000018569, registered 6 August 2015, https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000021492, and Japan Registry of Clinical Trials, jRCTs041180140, registered 29 March 2019, https://jrct.niph.go.jp/en-latest-detail/jRCTs041180140. This randomized controlled trial was conducted in accordance with the CONSORT guidelines.

    DOI： 10.1186/s12958-021-00866-2

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  4. Primate-specific POTE-actin gene could play a role in human folliculogenesis by controlling the proliferation of granulosa cells

    Kasahara Yukiyo, Osuka Satoko, Takasaki Nobuyoshi, Bayasula, Koya Yoshihiro, Nakanishi Natsuki, Murase Tomohiko, Nakamura Tomoko, Goto Maki, Iwase Akira, Kajiyama Hiroaki

    CELL DEATH DISCOVERY   Vol. 7 ( 1 ) page： 186   2021.7

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    Language：Japanese   Publisher：Cell Death Discovery  

    Patients with primary ovarian insufficiency (POI) often have a high prevalence of autoimmune disorders. To identify antigenic molecules associated with ovarian autoimmunity, we performed immunoprecipitation (IP) screening using serum from patients with POI and the established human granulosa cell line (HGrC1). POTE ankyrin domain family member E (POTEE) and POTE ankyrin domain family member F (POTEF), proteins specific to primates, were identified as candidate antigens. Using immunohistochemistry (IHC) with human ovarian tissue, POTEE or POTEF was weakly seen in the granulosa cells (GCs) of primordial follicles and primary follicles, and strongly in large antral follicles and luteal cells. Interestingly, no signals were detected in growing GCs in secondary, preantral, and small antral follicles. Thus, to explore the function of POTEE and POTEF in human folliculogenesis, we established HGrC1 cell lines with drug-inducible expression of POTEF. Expression of POTEF significantly suppressed cell proliferation in HGrC1 cells. Furthermore, chaperonin containing TCP-1 complex (CCT) components, which affect folding proteins required for cell proliferation, was bound to the actin domain of POTEF protein. Although CCT is normally localized only around the Golgi apparatus, TCP-1α, a component of CCT, co-migrated closer to the cell membrane when POTEF expression was induced. These data suggest that the interaction between POTEF and CCT components impairs the usual function of CCT during cell growth. In addition, over-accumulation of POTEF in HGrC1 cells leads to autophagic failure. It was recently reported that knockout of an autophagic gene in mice leads to a phenotype similar to human POI. These results suggested that a proper amount of POTEF is required for the maintenance of GCs in follicle pools, whereas POTEF overaccumulation might be involved in follicle atresia and the development of POI. We also showed the possibility that POTEF could be an antigen involved in ovarian autoimmunity.

    DOI： 10.1038/s41420-021-00566-1

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  5. Very Low Levels of Serum Anti-Mullerian Hormone as a Possible Marker for Follicle Growth in Patients with Primary Ovarian Insufficiency Under Hormone Replacement Therapy

    Kasahara Yukiyo, Osuka Satoko, Bayasula, Nakanishi Natsuki, Murase Tomohiko, Nakamura Tomoko, Goto Maki, Kotani Tomomi, Iwase Akira, Kikkawa Fumitaka

    REPRODUCTIVE SCIENCES   Vol. 28 ( 1 ) page： 31 - 36   2021.1

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    Publisher：Reproductive Sciences  

    DOI： 10.1007/s43032-020-00278-4

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  6. Establishment and characterization of cell lines from human endometrial epithelial and mesenchymal cells from patients with endometriosis

    Muraoka A., Osuka S., Kiyono T., Suzuki M., Yokoi A., Murase T., Nishino K., Niimi K., Nakamura T., Goto M., Kajiyama H., Kondo Y., Kikkawa F.

    F and S Science   Vol. 1 ( 2 ) page： 195 - 205   2020.11

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    Language：Japanese   Publisher：F and S Science  

    Objective: To establish and characterize cell lines derived from human endometrial epithelial cells (ECs) and mesenchymal cells (MCs) from patients with and without endometriosis. Design: In vitro experimental study. Setting: University and national cancer center research institute. Patient(s): Two women with endometriosis and two women without endometriosis. Intervention(s): Sampling of endometrial ECs and MCs. Main Outcome Measure(s): Establishing immortalized endometrial ECs and MCs with quantitative reverse transcription-polymerase chain reaction (qRT-PCR), immunocytochemical analysis, and RNA sequence profiling performed to characterize the immortalized cells and a cell proliferation assay, three-dimensional culture, and assays for hormone responses performed to characterize the features of ECs. Result(s): The qRT-PCR, immunocytochemical analysis, and Western blot analysis revealed that the ECs and MCs maintained their original features. Moreover, the immortalized cells were found to retain responsiveness to sex steroid hormones. The ECs formed a gland-like structure in three-dimensional culture, indicating the maintenance of normal EC phenotypes. The RNA sequence profiling, principal component analysis, and clustering analysis showed that the gene expression patterns of the immortalized cells were different from those of cancer cells. Several signaling pathways that were statistically significantly enriched in ECs and MCs with endometriosis were revealed. Conclusion(s): We successfully obtained four paired immortalized endometrial ECs and MCs from patients with and without endometriosis. Using these cells could help identify diagnostic and therapeutic targets for endometriosis. The cell lines established in this study will thus serve as powerful experimental tools in the study of endometriosis.

    DOI： 10.1016/j.xfss.2020.09.001

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  7. Novel ovarian endometriosis model causes infertility via iron-mediated oxidative stress in mice

    Hayashi Shotaro, Nakamura Tomoko, Motooka Yashiro, Ito Fumiya, Jiang Li, Akatsuka Shinya, Iwase Akira, Kajiyama Hiroaki, Kikkawa Fumitaka, Toyokuni Shinya

    REDOX BIOLOGY   Vol. 37   page： 101726   2020.10

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  8. Mutant FOXL2(C134W) Hijacks SMAD4 and SMAD2/3 to Drive Adult Granulosa Cell Tumors

    Weis-Banke Stine E., Lerdrup Mads, Kleine-Kohlbrecher Daniela, Mohammad Faizaan, Sidoli Simone, Jensen Ole N., Yanase Toshihiko, Nakamura Tomoko, Iwase Akira, Stylianou Anthe, Abu-Rustum Nadeem R., Aghajanian Carol, Soslow Robert, Paula Arnaud Da Cruz, Koche Richard P., Weigelt Britta, Christensen Jesper, Helin Kristian, Cloos Paul A. C.

    CANCER RESEARCH   Vol. 80 ( 17 ) page： 3466 - 3479   2020.9

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  9. Primary Follicles Suppress the Growth of Primordial Follicles.

    Wei Wei, Komatsu Kouji, Murase Tomohiko, Sonehara Reina, Miyake Natsuki, Murakami Mayuko, Ganieva Umida, Bayasula Bayasula, Yoshita Sayako, Muraoka Ayako, Hayashi Shotaro, Nakanishi Natsuki, Kasahara Yukiyo, Takasaki Nobuyoshi, Nakamura Tomoko, Osuka Satoko, Goto Maki, Kikkawa Fumitaka

    REPRODUCTIVE SCIENCES   Vol. 27 ( SUPPL 1 ) page： 283A - 283A   2020.3

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  10. The Function of POTEF in Human Granulosa Cells, an Antigen for Ovarian Autoimmunity, in POI Patients.

    Kasahara Yukiyo, Osuka Satoko, Takasaki Nobuyoshi, Wei Wei, Nakanishi Natsuki, Bayasula Bayasula, Nakamura Tomoko, Murase Tomohiko, Goto Maki, Kikkawa Fumitaka

    REPRODUCTIVE SCIENCES   Vol. 27 ( SUPPL 1 ) page： 199A - 199A   2020.3

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  11. 若年者における子宮内膜症 Reviewed

    中村 智子

    東海産婦人科内視鏡手術研究会雑誌   Vol. 8   page： 3 - 9   2020

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  12. Appendiceal intussusception from endometriosis

    Nakamura Tomoko, Hayashi Shotaro, Shimizu Ken, Muraoka Ayako, Nakanishi Natsuki, Niimi Kaoru, Osuka Satoko, Goto Maki

    JAPANESE JOURNAL OF GYNECOLOGIC AND OBSTETRIC ENDOSCOPY   Vol. 36 ( 1 ) page： 185 - 188   2020

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    Publisher：JAPAN SOCIETY OF GYNECOLOGIC AND OBSTETRIC ENDOSCOPY AND MINIMALLY INVASIVE THERAPY  

    <p>  Appendiceal intussusception secondary to endometriosis is extremely rare. We report a case of left ovarian endometriosis with endometriosis-induced appendiceal intussusception in a 42-year-old woman presenting with rectal bleeding and left-sided abdominal pain. Colonoscopy revealed a cecal mass measuring 30 mm in diameter. Magnetic resonance imaging revealed extensive pelvic adhesions and a left-sided endometrioma measuring 20 mm in diameter. Laparoscopy revealed isolated appendiceal intussusception and deep infiltrating pelvic endometriosis. Laparoscopic ileocecal resection and left ovarian cystectomy were performed. Histopathological examination confirmed the diagnosis of ovarian endometriosis with endometriosis-induced appendiceal intussusception. Although rare, endometriosis-induced appendiceal intussusception should be considered in the differential diagnosis in women with endometriosis presenting with an appendiceal mass. Coordination between gynecologists and gastrointestinal surgeons is essential for an effective surgical approach to ensure optimal management.</p><p></p>

    DOI： 10.5180/jsgoe.36.1_185

  13. Upregulation of Fibroblast Growth Factors Caused by Heart and Neural Crest Derivatives Expressed 2 Suppression in Endometriotic Cells: A Possible Therapeutic Target in Endometriosis.

    Kato N, Iwase A, Ishida C, Nagai T, Mori M, Bayasula, Nakamura T, Osuka S, Ganiyeva U, Qin Y, Miki R, Kikkawa F

    Reproductive sciences (Thousand Oaks, Calif.)   Vol. 26 ( 7 ) page： 979 - 987   2019.7

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

    DOI： 10.1177/1933719118802053

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  14. Molecular mechanism of FSHR expression induced by BMP15 in human granulosa cells

    Shimizu Ken, Nakamura Tomoko, Bayasula, Nakanishi Natsuki, Kasahara Yukiyo, Nagai Takashi, Murase Tomohiko, Osuka Satoko, Goto Maki, Iwase Akira, Kikkawa Fumitaka

    JOURNAL OF ASSISTED REPRODUCTION AND GENETICS   Vol. 36 ( 6 ) page： 1185 - 1194   2019.6

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  15. Protective effects of mangafodipir against chemotherapy-induced ovarian damage in mice

    Qin Ying, Iwase Akira, Murase Tomohiko, Bayasula, Ishida Chiharu, Kato Nao, Nakamura Tomoko, Osuka Satoko, Takikawa Sachiko, Goto Maki, Kotani Tomomi, Kikkawa Fumitaka

    REPRODUCTIVE BIOLOGY AND ENDOCRINOLOGY   Vol. 16 ( 1 ) page： 106   2018.10

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

    DOI： 10.1186/s12958-018-0426-y

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  16. TCF21 REGULATION OF PERIOSTIN IN THE PROGRESSION OF ENDOMETRIOTIC FIBROSIS.

    Ganieva U., Nakamura T., Nguyen P. X., Wei W., Murakami M., Miyake N., Nakanishi N., Kasahara Y., Takasaki N., Muraoka A., Hayashi S., Nagai T., Murase T., Osuka S., Goto M., Iwase A.

    FERTILITY AND STERILITY   Vol. 110 ( 4 ) page： E393 - E393   2018.9

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  17. Thyroid Autoantibodies do not Impair the Ovarian Reserve in Euthyroid Infertile Women: A Cross-Sectional Study

    Osuka Satoko, Iwase Akira, Goto Maki, Takikawa Sachiko, Nakamura Tomoko, Murase Tomohiko, Kato Nao, Bayasula, Kotani Tomomi, Kikkawa Fumitaka

    HORMONE AND METABOLIC RESEARCH   Vol. 50 ( 7 ) page： 537-542   2018.7

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

    DOI： 10.1055/a-0637-9430

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  18. Neuropeptide phoenixin (PNX) and its novel receptor GPR173 induce COX-1/COX-2 expression and PGE2 production through the CREB signaling pathway

    Nguyen X. P., Iwase A., Murase T., Ganieva U., Qin Y., Bayasula B., Shimizu K., Osuka S., Nakamura T., Goto M., Kikkawa F.

    HUMAN REPRODUCTION   Vol. 33   page： 287 - 287   2018.7

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  19. Clinical application of serum anti-Müllerian hormone as an ovarian reserve marker: A review of recent studies.

        2018.3

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

    DOI： 10.1111/jog.13633

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  20. FOXL2C134W-induced CYP19 expression via cooperation with SMAD3 in HGrC1 cells.

    Belli M, Iwata N, Nakamura T, Iwase A, Stupack D, Shimasaki S

    Endocrinology     2018.2

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

    DOI： 10.1210/en.2017-03207

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  21. Follicle dynamics: visualization and analysis of follicle growth and maturation using murine ovarian tissue culture.

    Murase T, Iwase A, Komatsu K, Bayasula, Nakamura T, Osuka S, Takikawa S, Goto M, Kotani T, Kikkawa F

    Journal of assisted reproduction and genetics   Vol. 35 ( 2 ) page： 339-343   2018.2

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

    DOI： 10.1007/s10815-017-1073-5

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  22. Two cases of bladder endometriosis treated using cystoscopy-assisted laparoscopic partial cystectomy

    Ishida Chiharu, Muraoka Ayako, Murase Tomohiko, Nakamura Tomoko, Osuka Satoko, Goto Maki, Nomoto Masataka, Iwase Akira

    JAPANESE JOURNAL OF GYNECOLOGIC AND OBSTETRIC ENDOSCOPY   Vol. 34 ( 2 ) page： 204-210   2018

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

    <p>  Bladder endometriosis is a rare pelvic dysfunction with painful urination and hematuria.</p><p>  We successfully managed two cases of bladder endometriosis by cystoscopy-assisted laparoscopic partial cystectomy. </p><p><b>Case 1:</b> A 40-year-old woman presented with urodynia during menstruation for four years. Cystoscopy revealed a dark-red polypoid lesion on the posterior bladder wall. She underwent hormonal therapy with GnRH-agonist for six months followed by dienogest for a few months. She finally decided to undergo an operation because of poor improvement of symptoms. Incision line was determined using cystoscopy with a margin from both ureteral orifices and then laparoscopic partial cystectomy was performed. She was discharged after confirmation of no leakage by cystography at post-operative day 7. </p><p><b>Case 2:</b> A 44-year-old woman was diagnosed with endometriosis at the age of 30 and had been taking low dose estrogen and progestin (LEP). She discontinued LEP owing to breast cancer and then started to feel pain during menstruation, urination, and defecation. Cystoscopy revealed a polypoid lesion on the posterior bladder wall. She underwent laparoscopic hysterectomy, bilateral salpingo-oophorectomy, and cystoscopy-assisted partial cystectomy. Her postoperative course was uneventful, and she was discharged at post-operative day 8. Altogether, this case report suggests that using cystoscopy to avoid unnecessary ureterovesicostomy and maintaining adequate distance from both ureteral orifices is useful to determine the incision line. Cooperation with urologists is necessary when performing surgery in patients with bladder endometriosis.</p>

    DOI： 10.5180/jsgoe.34.2_204

  23. Retrospective analysis of magnetic resonance imaging for differentiating intraligamentous leiomyomas from subserosal leiomyomas

    Shimizu Ken, Iwase Akira, Sakurai Yusuke, Nakamura Tomoko, Osuka Satoko, Takikawa Sachiko, Goto Maki, Kikkawa Fumitaka

    EUROPEAN JOURNAL OF OBSTETRICS & GYNECOLOGY AND REPRODUCTIVE BIOLOGY   Vol. 215   page： 256 - 257   2017.8

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    DOI： 10.1016/j.ejogrb.2017.06.046

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  24. PAI-1 in granulosa cells is suppressed directly by statin and indirectly by suppressing TGF- and TNF- in mononuclear cells by insulin-sensitizing drugs

    Yamada-Nomoto Kaori, Yoshino Osamu, Akiyama Ikumi, Iwase Akira, Ono Yosuke, Nakamura Tomoko, Harada Miyuki, Nakashima Akitoshi, Shima Tomoko, Ushijima Akemi, Osuga Yutaka, Chang Russell Jeffrey, Shimasaki Shunichi, Saito Shigeru

    AMERICAN JOURNAL OF REPRODUCTIVE IMMUNOLOGY   Vol. 78 ( 1 )   2017.7

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    DOI： 10.1111/aji.12669

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  25. Analysis of Follicular Growth and Oocyte Maturation in Cultured Murine Ovarian Tissue.

    Murase Tomohiko, Iwase Akira, Nguyen Phuoc Xuan, Ganieva Umida, Qin Ying, Nakanishi Natsuki, Kasahara Yukiyo, Nagai Takashi, Shimizu Ken, Ishida Chiharu, Kato Nao, Osuka Satoko, Nakamura Tomoko, Takikawa Sachiko, Goto Maki, Kikkawa Fumitaka

    REPRODUCTIVE SCIENCES   Vol. 24   page： 292A-292A   2017.3

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  26. Growth Differentiation Factor 9 Induces Granulosa Cell Proliferation via Inhibition of the Expression of AMH Type II Receptor.

    Iwase Akira, Osuka Satoko, Bayasula Bayasula, Takikawa Sachiko, Murase Tomohiko, Nakamura Tomoko, Goto Maki, Kikkawa Fumitaka

    REPRODUCTIVE SCIENCES   Vol. 24   page： 163A-163A   2017.3

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  27. Kisspeptin in the Hypothalamus of 2 Rat Models of Polycystic Ovary Syndrome

    Osuka Satoko, Iwase Akira, Nakahara Tatsuo, Kondo Mika, Saito Ai, Bayasula, Nakamura Tomoko, Takikawa Sachiko, Goto Maki, Kotani Tomomi, Kikkawa Fumitaka

    ENDOCRINOLOGY   Vol. 158 ( 2 ) page： 367-377   2017.2

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    DOI： 10.1210/en.2016-1333

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  28. CYP51A1 induced by growth differentiation factor 9 and follicle-stimulating hormone in granulosa cells is a possible predictor for unfertilization Reviewed

    Nakamura T, Iwase A, Bayasula B, Nagatomo Y, Kondo M, Nakahara T, Takikawa S, Goto M, Kotani T, Kiyono T, Kikkawa F

    Reproductive sciences   Vol. 22 ( 3 ) page： 377-84   2015.3

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

    DOI： 10.1177/1933719114529375.

  29. A Placental Site Trophoblastic Tumor Complicated with Arteriovenous Malformation: A Case Report

    Tomoko Nakamura, Akira Iwase, Chiharu Ishida, Sachiko Takikawa, Maki Goto, Fumitaka Kikkawa

    Clinical Case Reports   Vol. 5 ( 9 )   2015

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

    DOI： 10.4172/2165-7920.1000596

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To the head of Papers.▲

KAKENHI (Grants-in-Aid for Scientific Research) 5

  1. 顆粒膜細胞障害に着目した子宮内膜症における卵胞発育障害の解明

    Grant number：20K09615  2020.4 - 2023.3

    中村 智子

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    Authorship：Principal investigator 

    Grant amount：\4420000 （ Direct Cost: \3400000 、 Indirect Cost：\1020000 ）

    内膜症による卵胞発育障害の機序を、炎症と線維化による顆粒膜細胞障害から解明し、排卵を抑制しない新規内膜症治療薬の開発を目的とする。機序の解明に際し、効果的な阻害剤や補充療法を選定し、マウスモデルを用いて新規治療薬としての効果判定を行う。他疾患と共通する機序が見出されれば、既存の臨床治療薬が内膜症治療に応用可能か調べる。さらに内膜症に限らず、同じく線維化が主病態である卵巣の加齢・早発機能不全(POF)・がん生殖においても卵胞機能保全の方策の一助とする。

  2. リプロダクティブヘルスケア/ライツ啓発を組み入れた新規早発卵巣不全予測法の検証

    Grant number：20K11508  2020.4 - 2023.3

    後藤 真紀

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    Authorship：Coinvestigator(s) 

    若い世代への加齢による卵の質の低下や卵巣予備能の啓発は重要である。また早発卵巣不全という疾患は40 歳未満で 1-2/100の発症率と稀な疾患ではないが、原因不明であり発症後の治療や自己卵子での妊娠が非常に困難となる疾患である。本研究では講義形式のみの受動的な啓発手法に加えて、能動的に卵巣予備能を測定し自身の卵巣予備能について認識してもらう啓発プログラムの有効性を検証し、早発卵巣不全ハイリスク患者の抽出とリスク因子を解析することで、早発卵巣不全の早期発見を可能にするスクリーニング法の開発と検証を同時に行う。

  3. 新規子宮内膜症モデルと線維化セルリネッジによるドライバー変異発生機序の探索

    Grant number：19K22674  2019.6 - 2021.3

    挑戦的研究(萌芽)

    岩瀬 明

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    Authorship：Coinvestigator(s) 

    子宮内膜症は子宮内膜類似組織が子宮外に認められ、炎症や線維化等をきたし、月経痛、卵巣癌等の原因となる。逆流子宮内膜細胞移植説が提唱されているが、病因病態の詳細は不明である。本研究では、子宮内膜症の本態は異所性に生着した内膜細胞の筋線維芽細胞変化であると捉え、TCF21陽性セルリネッジが筋線維芽細胞変化、癌関連遺伝子変異にも関与するとする仮説を証明するため、in vivo/in vitro実験および、in vivoでTCF21遺伝子を導入する新しいマウスモデルを用い、TCF21セルリネッジにおける筋線維芽細胞変化とその機序、組織線維化とDNA損傷、癌関連遺伝子変異の関連について探索する。
    1)TCF21発現と局所炎症、ECM産生・線維化との関連
    正所性子宮内膜（内膜症合併有・無）、子宮内膜症（腹膜病変・卵巣子宮内膜症性嚢胞・深部内膜症）組織を用いTCF21発現を評価した。発現は弱い順に、子宮内膜症合併無し正所性子宮内膜＜子宮内膜症合併有り正所性子宮内膜＜腹膜病変＜卵巣子宮内膜症性嚢胞＜深部内膜症であった。これは病変局所の炎症・線維化の重症度と相関していると予測された。二重染色データでは、TCF21とIL-4,-13, TGFbとの共局在をみとめた。また病変組織から分離培養した正所性子宮内膜間質細胞、子宮内膜症間質細胞でのTCF21発現についても、組織染色と一致する傾向をみとめた。培養子宮内膜症間質細胞では、IL-4,-13でTCF21発現が誘導されることを見出した。子宮内膜症間質細胞でのTCF21発現をsiRNAで抑制したところ、細胞の増殖能、浸潤能が低下することを見出した。
    2)TCF21発現とDNA損傷・癌関連遺伝子変異との関連
    正常子宮内膜および子宮内膜症病変（卵巣癌併存有・無）からレーザーマイクロダイセクションにて上皮細胞を分取しDNAおよびRNAを採取した。またレーザーマイクロダイセクションに用いた切片の線維化をマッソントリクローム染色で、低酸素マーカー(HIF-1a)を免疫組織染色で評価した。
    3)遺伝子追加導入による新規子宮内膜症モデル作製
    予定通り自家細切子宮移植により腹腔内に異所性子宮内膜組織が生着することを確認した。in vivo遺伝子導入ベクターについては、現在調整中であり早期の完成を目指す。
    本来初年度には、2)TCF21発現とDNA損傷・癌関連遺伝子変異との関連に関して、レーザーマイクロダイセクションで得られた検体の網羅的解析（RNAseq, 全エクソーム解析）を行う予定であったが、卵巣癌併存有無での検体選定に慎重な病理学的評価を行ったこと、倫理委員会での承認に時間を要したことにより、2年目に持ち越しになった。5月中には行える予定であったが新型コロナウイルス感染症の感染拡大により実験を停止しており、もう少し遅くなる見込みである。
    その他の実験については計画当初の予定通り進んでいる。
    1) TCF21発現とEMT, 筋線維芽細胞変化、ECM産生の関連
    TCF21抑制による細胞の表現型変化を確認するために、twist, snailなどの発現解析（EMT）、αSMA発現解析（筋線維芽細胞への変化）、コラーゲン・フィブロネクチン・ペリオスチンなどのECM産生（組織線維化惹起）について比較検討する。
    2) TCF21発現とDNA損傷・癌関連遺伝子変異との関連
    正常子宮内膜および子宮内膜症病変からレーザーマイクロダイセクションにて上皮細胞を分取し採取したDNAおよびRNAを用い網羅的解析を行う。DNAについては、ARID1A, KRAS, PIK3CA, PTEN等の遺伝子変異有無に着目する。DNA損傷については連続切片における53BP1の免疫染色で評価する。抽出RNAについてはRNAseqを行う。以上より総合的に、TCF21陽性セルリネッジでの線維化変化と低酸素環境、DNA変異についての関連解析を行う。
    3) 遺伝子追加導入による新規子宮内膜症モデル作製
    異所性子宮内膜生着マウスにin vivo遺伝子導入用ベクターを腹腔内投与する。異所性子宮内膜細胞でのTCF21発現を促進した結果、ヒト子宮内膜症類似の病変の線維化およびDNAの損傷が亢進したかどうか検証する。

  4. The regulation of FSHR expression during folliculogenesis

    Grant number：18K16767  2018.4 - 2020.3

    Grant-in-Aid for Early-Career Scientists

    Nakamura Tomoko

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    Authorship：Principal investigator 

    Grant amount：\3900000 （ Direct Cost: \3000000 、 Indirect Cost：\900000 ）

    Our study elucidated the effects of Bone Morphogenetic Protein 15 (BMP15) and the novel neuropeptide phoenixin which induces follicle stimulating hormone receptor (FSHR) expression in　human granulosa cells. BMP15 elevates FSHR expression in human granulosa cells by epigenetically modifying the promoter region of the FSHR gene through both Smad and non-Smad pathways. Phoenixin accelerates granulosa cell proliferation and increases steroid production as well as inducing FSHR expression. Murine ovarian tissue culture showed that phoenixin stimulates follicle growth and increases ovulation, thereby describing the role of phoenixin in the ovary.

  5. Elucidation of folliculogenesis by spatio-temporal investigation

    Grant number：15H04984  2015.4 - 2018.3

    Iwase Akira

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    Authorship：Coinvestigator(s) 

    The purpose of our project was to analyze the mechanism of early follicle development and consequently develop new drugs for ovarian stimulation and ex vivo ovarian tissue culture system.
    We established visualized murine ovarian tissue culture system and identified GDF-9, bFGF and IGF-1 as a stimulating factor and AMH as an inhibiting factor for follicle development. We also identified kisspeptin and phonexin as a novel peptide factor inducing follicle development.
    We demonstrated that the factors mentioned above induced follicle development in ex vivo murine ovarian tissue culture and efficiently produced matured oocytes. However, the investigation using human ovarian tissues revealed that ex vivo-induction of follicle development was not feasible because of the differences in ovarian sizes and follicle growth cycles.

To the head of KAKENHI (Grants-in-Aid for Scientific Research).▲