Studies on lower urinary tract dysfunction pathogenesis by complex systems network and dynamic homeostasis collapse

• Project/Area Number: 15H04972
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Urology
• Research Institution: University of Yamanashi
• Principal Investigator: TAKEDA Masayuki 山梨大学, その他部局等, 理事 (80197318)
• Co-Investigator(Kenkyū-buntansha): 小泉 修一 山梨大学, 大学院総合研究部, 教授 (10280752) ; 富永 真琴 大学共同利用機関法人自然科学研究機構(岡崎共通研究施設), 岡崎統合バイオサイエンスセンター, 教授 (90260041)
• Co-Investigator(Renkei-kenkyūsha): YOSHIYAMA Mitsuharu 山梨大学, 大学院総合研究部, 医学研究員 (20422694) ; SAWADA Norifumi 山梨大学, 大学院総合研究部, 講師 (70402055) ; KIRA Satoru 山梨大学, 大学院総合研究部, 助教 (10530115) ; IHARA Tatsuya 山梨大学, 大学院総合研究部, 助教 (90622407)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥16,640,000 (Direct Cost: ¥12,800,000、Indirect Cost: ¥3,840,000); Fiscal Year 2017: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2016: ¥5,850,000 (Direct Cost: ¥4,500,000、Indirect Cost: ¥1,350,000); Fiscal Year 2015: ¥6,110,000 (Direct Cost: ¥4,700,000、Indirect Cost: ¥1,410,000)
• Keywords: Lower urinary tract / Clock genes / Mechanosensor / Metabolomics / Biomarker / nocturia / clock gene / noctrunal polyuria / metabolomics / 下部尿路機能障害 / 複雑系ネットワーク / 動的恒常性破綻 / 発症機序 / P2Y6受容体欠損マウス / 時計遺伝子異常 / 夜間頻尿 / ＴＲＰチャネル / 排尿機能学 / 下部尿路機能 / 動的恒常性 / 時計遺伝子 / 機械センサー

Outline of Final Research Achievements

We demonstrated that ClockD19/D19 mice showed the phenotype of NOC/NP. The ClockD19/D19 mouse may be used as an animal model of NOC and NP.The gene expression of mechanosensor, Cx26 and VNUT was maintained at a higher level in spite of the sleep phase.We demonstrated that the time-dependent gene expressions, including clock genes, mechano-sensors, and ARMM, were reproducible in UCs. These findings demonstrated that UCs have the potential to progress research into the circadian functions of the lower urinary tract regulated by clock genes.The expressions of Cxs and TRP channels on urothelial cells in voided urine could be related to LUTS. Male lower urinary tract symptoms may develop due to abnormalmetabolic processes in some pathways. Potential new treatments for lower urinary tract symptoms can be developed by identifying changes in the amino acid profiles.

Research Products

• [Journal Article] Metabolomics Approach to Male Lower Urinary Tract Symptoms: Identification of Possible Biomarkers and Potential Targets for New Treatments (2018)
  • Author(s): Mitsui Takahiko、Kira Satoru、Ihara Tatsuya、Sawada Norifumi、Nakagomi Hiroshi、Miyamoto Tatsuya、Shimura Hiroshi、Yokomichi Hiroshi、Takeda Masayuki
  • Journal Title: The Journal of Urology Volume: 199 Issue: 5 Pages: 1312-1318
  • DOI: 10.1016/j.juro.2017.11.070
  • Peer Reviewed / Open Access
• [Journal Article] Clock Genes Regulate the Circadian Expression of Piezo1, TRPV4, Connexin26, and VNUT in an Ex Vivo Mouse Bladder Mucosa. (2017)
  • Author(s): 5.Ihara T, Mitsui T, Nakamura Y, Kira S, Nakagomi H, Sawada N, Hirayama Y, Shibata K, Shigetomi E, Shinozaki Y, Yoshiyama M, Andersson KE, Nakao A, Takeda M, Koizumi S
  • Journal Title: PLoS One Volume: 12 Issue: 1 Pages: e0168234-e0168234
  • DOI: 10.1371/journal.pone.0168234
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The Circadian expression of Piezo1, TRPV4, Connexin26, and VNUT, associated with the expression levels of the clock genes in mouse primary cultured urothelial cells (2017)
  • Author(s): Ihara Tatsuya、Mitsui Takahiko、Nakamura Yuki、Kanda Mie、Tsuchiya Sachiko、Kira Satoru、Nakagomi Hiroshi、Sawada Norifumi、Hirayama Yuri、Shibata Keisuke、Shigetomi Eiji、Shinozaki Yoichi、Yoshiyama Mitsuharu、Nakao Atsuhito、Takeda Masayuki、Koizumi Schuichi
  • Journal Title: Neurourology and Urodynamics Volume: 37 Issue: 3 Pages: 942-951
  • DOI: 10.1002/nau.23400
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] P2Y6-deficiency increases micturition frequency and attenuates sustained contractility of the urinary bladder in mice (2017)
  • Author(s): Kira S,Yoshiyama M,Tsuchiya S,Shigetomi E,Miyamoto T,Nakagomi H,Shibata K,Mochizuki T,Takeda M,Koizumi S
  • Journal Title: Scientific Reports Volume: 7 Issue: 1 Pages: 771-771
  • DOI: 10.1038/s41598-017-00824-2
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Detrusor pressures in urodynamic studies during voiding in women (2017)
  • Author(s): Kira S,Mitsui T,Kobayashi H,Haneda Y,Sawada N,Takeda M
  • Journal Title: Int Urogynecol J Volume: 28 Issue: 5 Pages: 783-787
  • DOI: 10.1007/s00192-016-3203-5
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Carbenoxolone inhibits TRPV4 channel-initiated oxidative urothelial injury and ameliorates cyclophosphamide-induced bladder dysfunction (2017)
  • Author(s): Zhang X,Gao S,Tanaka M,Zhanq Z,Huanq Y,Mitsui T,Kamiyama M,Koizumi S,Fan J,Takeda M,Yao J
  • Journal Title: J Cell Mol Med Volume: 2017 Issue: 9 Pages: 346-346
  • DOI: 10.1111/jcmm.13100
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] AMPK Suppresses Connexin43 Expression in the Bladder and Ameliorates Voiding Dysfunction in Cyclophosphamide-induced Mouse Cystitis (2016)
  • Author(s): Zhang X, Yao J, Gao K, Chi Y, Mitsui T, Ihara T, Sawada N, Kamiyama M, Fan J, Takeda M
  • Journal Title: Sci Rep. Volume: 6 Issue: 1 Pages: 19708-19708
  • DOI: 10.1038/srep19708
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] The Clock mutant mouse is a novel experimental model for nocturia and nocturnal polyuria. (2016)
  • Author(s): Ihara, T., Mitsui, T., Nakamura, Y., Kira, S., Miyamoto, T., Nakagomi, H., Sawada, N., Hirayama, Y., Shibata, K., Shigetomi, E., Shinozaki, Y., Yoshiyama, M., Nakao, A., *Takeda, M. *Koizumi, S.
  • Journal Title: Neurourology and Urodynamics Volume: 36 Issue: 4 Pages: 1034-1038
  • DOI: 10.1002/nau.23062
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Urothelial ATP exocytosis: regulation of bladder compliance in the urine storage phase (2016)
  • Author(s): Nakagomi H,Yoshiyama M,Mochizuki T,Miyamoto T,Komatsu R,Imura Y,Morizawa Y,Hiasa M,Kira S,Fujishita K,Shibata K,Shigetomi E,Shinozaki Y,Takeda M,Koizumi S
  • Journal Title: Scientific Reports Volume: 6 Issue: 1 Pages: 29761-29761
  • DOI: 10.1038/srep29761
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Muscarinic Binding of the Novel Radioligand, [3H] Imidafenacin in the Hauman Bladder and Protid Gland, (2015)
  • Author(s): Akira Yoshida, Shiori Kuroda, Yoshiki Ito, Takashi Okura, Yoshiharu Deguchi, Atsushi Otsuka, Seiichiro Ozono, Masayuki Takeda, Isao Araki, Shizuo Yamada
  • Journal Title: J Pharmacol Sci Volume: 124 Pages: 40-46
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Yamaguchi O, Marui H, Kakizaki H, Homma Y, Igawa Y, Takeda M, Nishizawa O, Gotoh M, Yoshida Y, Yokoyama O, Seki N, Ikeda Y, Ohkawa S (2015)
  • Author(s): Yamaguchi O, Marui H, Kakizaki H, Homma Y, Igawa Y, Takeda M, Nishizawa O, Gotoh M, Yoshida Y, Yokoyama O, Seki N, Ikeda Y, Ohkawa S
  • Journal Title: BJU Int Volume: 113 Pages: 951-960
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Tadalafil 5 mg once-daily therapy for men with lower urinary tract symptoms suggestive of benign prostatic hyperplasia: Results from a randomized, double-blind, placebo-controlled trial performed in Japan and the Republic of Korea (2015)
  • Author(s): Masayuki Takeda, Yokoyam, Sung Won Lee, Masahiro Murakami, Yoji Morisaki, Lars Viktrup
  • Journal Title: Int J of Urol Volume: 21 Pages: 670-675
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Suppression of cell membrane permeability by suramin: involvement of its (2015)
  • Author(s): Yuan Chi, Kun Gao, Hui Zhang, Masayuki Takeda and Jian Yao
  • Journal Title: Brit J Pharmacol Volume: 171 Pages: 3448-3462
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Purinergic control of AMPK activation by ATP released through connexin 43 hemichannels – pivotal roles in hemichannel-mediated cell injury (2015)
  • Author(s): Yuan Chi, Kun Gao, Kai Li, Shotaro Nakajima, Satoru Kira, Masayuki Takeda and Jian Yao
  • Journal Title: J Cell Sci Volume: 127 Pages: 1487-1499
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Presentation] Session 22(Podium Poster)- Mechanisms Underlying Pain and Cystitis: Session chair (2015)
  • Author(s): Masayuki Takeda
  • Organizer: 44th Annual Meeting of the International Continence Society
  • Place of Presentation: RiodeJaneiro(Brazil)
  • Year and Date: 2015-10-05
  • Int'l Joint Research / Invited
• [Presentation] State of Art Lecture III: Chair (2015)
  • Author(s): Masayuki Takeda
  • Organizer: The 9th of Pan-Pacific Continence Society Meeting, Taichung, Taiwan
  • Place of Presentation: Taichung(Taiwan)
  • Year and Date: 2015-09-14
  • Int'l Joint Research / Invited
• [Presentation] Relationship between nocturnal bladder capacity and nocturia in BPH/OAB patients with alpha1-blocker and anticholinergic drug treatment; Post-hoc analysis of Addition study (2015)
  • Author(s): Masaki Yoshida, Masayuki Takeda, Osamu Nishizawa, Momokazu Gotoh, Satoru Takahashi, Naoya Masumori
  • Organizer: 29th Annual EAU Congress
  • Place of Presentation: Stockholm(Sweden)
  • Year and Date: 2015-04-01
  • Int'l Joint Research
• [Presentation] Purinergic transmission via P2Y6 receptor plays an essential role in bladder storage function in mice (2015)
  • Author(s): Satoru Kira, Mitsuharu Yoshiyama, Tatsuya Miyamoto, Hiroshi Nakagomi, Tsutomu Mochizuki, Eiji Shigetomi, Schuichi Koizumi, Masayuki Takeda
  • Organizer: 29th Annual EAU Congress
  • Place of Presentation: Stockholm(Sweden)
  • Year and Date: 2015-04-01
  • Int'l Joint Research
• [Presentation] Inhibition of Piezo1 in bladder urothelium: A potential therapy for overactive bladder (2015)
  • Author(s): Tatsuya Miyamoto, Hiroshi Nakagomi, Tatsuya Ihara ,Satoru Kira, Tsutomu Mochizuki, Makoto Tominaga, Masayuki Takeda
  • Organizer: 29th Annual EAU Congress
  • Place of Presentation: Stockholm(Sweden)
  • Year and Date: 2015-04-01
  • Int'l Joint Research
• [Book] 1.UAA Consensus on the Management of BPH/Male LUTS 1st Edition、Masayuki Takeda (委員長)、Urological Association of Asia, 1-136, 2014 (2015)
  • Author(s): Masayuki Takeda et al
  • Publisher: Urological Association of Asia
• [Book] 間質性膀胱炎：今日の治療指針 (2015)
  • Author(s): 武田正之
  • Total Pages: 1048
  • Publisher: 医学書院
• [Book] 排尿障害治療薬、ポケット版治療薬UP-TO-DATE2014、620-620 (2015)
  • Author(s): 武田正之
  • Total Pages: 1256
  • Publisher: メデイカルビュー社
• [Book] 低活動膀胱、プライマリ・ケア医のためのLUTS診療ハンドブック、101-113 (2015)
  • Author(s): 小林英樹、武田正之
  • Total Pages: 215
  • Publisher: 中外医学社
• [Patent(Industrial Property Rights)] 睡眠期頻尿のモデル、評価方法 (2017)
  • Inventor(s): 井原達矢
  • Industrial Property Rights Holder: 井原達矢
  • Industrial Property Rights Type: 特許
  • Filing Date: 2017