海綿体神経損傷モデルにおけるオートファジーと神経栄養因子の分子相互作用の解明

• Project/Area Number: 26462453
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Urology
• Research Institution: Juntendo University
• Principal Investigator: 久末 伸一 順天堂大学, 医学部, 准教授 (90404673)
• Project Period (FY): 2014-04-01 – 2016-03-31
• Project Status: Discontinued (Fiscal Year 2015)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2016: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2015: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2014: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: オートファジー / 糖尿病 / 勃起障害 / 海綿体神経 / PEDF / PDE5阻害薬 / nNOS

Outline of Annual Research Achievements

本研究でEDモデルでの海綿体神経・陰茎海綿体における神経栄養因子neurturin発現の変化とそれに影響を及ぼす因子としてオートファジー活性と内分泌環境を分析し、勃起能回復低下のメカニズムを解明する。26年度は代表的なオートファジーマーカーであるLC3A-B I/II、BECN1について陰茎の幹部、根部、骨盤神経節での発現をWesternブロッティングにて確認したが、EDモデル、正常モデル、PDE5阻害薬モデルの各検討時期で有意な差を認めなかった。27年度は糖尿病ラットを用いてEDモデルを作成し、オートファジー活性マーカーからヒト色素上皮由来因子(PEDF, Pigment epithelium-derived factor glycoprotein)まで検索範囲を広げて各変化を確認した。
Masson Trichrome染色を用いて陰茎海綿体の平滑筋とコラーゲン線維の比を確認したところ有意な平滑筋量維持効果も確認できた。NO活性を評価する目的にeNOS、nNOSの発現を陰茎の幹部、根部、骨盤神経節において確認したところWesternブロッティングにてEDモデル、正常モデル、PDE5阻害薬投与モデルにおいてnNOSのみ骨盤神経節での有意な変化を認めた。また、PEDFは陰茎海綿体において糖尿病モデルでは発言が増強し、PDE5阻害薬によって減弱した。以上よりPDE5阻害薬はPEDFによる虚血性血管新生阻害を抑制し、血管新生を促している可能性が考えられた。この結果は今後、海綿体神経障害後のリハビリテーションにおけるPDE%阻害薬の新しい役割を位置づけるものと考えられた。

Research Products

• [Journal Article] Impact of aging and comorbidity on the efficacy of low-intensity shock wave therapy for erectile dysfunction. (2016)
  • Author(s): Hisasue S, China T, Horiuchi A, Kimura M, Saito K, Isotani S, Ide H, Muto S, Yamaguchi R, Horie S.
  • Journal Title: Int J Urol. Volume: 23(1) Issue: 1 Pages: 80-84
  • DOI: 10.1111/iju.12955
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Novel insight for midline cyst formation in prostate: The involvement of decreased prenatal testosterone suggested by second-to-forth digit ratio study (2015)
  • Author(s): Furuya S, Hisasue S, Kato H, Shimamura S
  • Journal Title: International Journal of Urology Volume: 22 Issue: 11 Pages: 1063-1067
  • DOI: 10.1111/iju.12892
  • Peer Reviewed / Open Access
• [Journal Article] The Impact of Increased Bladder Blood Flow on Storage Symptoms after Holmium Laser Enucleation of the Prostate. (2015)
  • Author(s): Saito K, Hisasue S, Ide H, Aoki H, Muto S, Yamaguchi R, Tsujimura A, Horie S.
  • Journal Title: PLoS One. Volume: 10(6) Issue: 6 Pages: e0129111-e0129111
  • DOI: 10.1371/journal.pone.0129111
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Testosterone replacement alters the cell size in visceral fat but not in subcutaneous fat in hypogonadal aged male rats as a late-onset hypogonadism animal model. (2015)
  • Author(s): Abdelhamed A, Hisasue S, Shirai M, Matsushita K, Wakumoto Y, Tsujimura A, Tsukamoto T, Horie S.
  • Journal Title: Res Rep Urol. Volume: 7 Pages: 35-40
  • DOI: 10.2147/rru.s72253
  • Peer Reviewed / Open Access
• [Journal Article] Correlation between erection hardness score and nocturnal penile tumescence measurement. (2014)
  • Author(s): Matsuda Y, Hisasue S, Kumamoto Y, Kobayashi K, Hashimoto K, Sato Y, Masumori N.
  • Journal Title: J Sex Med. Volume: 9 Issue: 9 Pages: 2272-2276
  • DOI: 10.1111/jsm.12617
  • Peer Reviewed
• [Journal Article] Impact of visceral fat ratio on sleep-related erection: a retrospective study of elderly patients. (2014)
  • Author(s): Takeuchi M, Hisasue S, Hashimoto K, Tsukamoto T, Masumori N.
  • Journal Title: Int J Urol. Volume: 10 Issue: 10 Pages: 1046-50
  • DOI: 10.1111/iju.12497
• [Presentation] Testosterone gel treatment significantly ameliorates urinary urgency and sleep disturbance: double-blind, placebo-controlled clinical trial (2015)
  • Author(s): Shin-ichi Hisasue, Hisamitsu Ide, Naoya Nagaya, Masaki Kimura, Amr Abdelhamed, Masato Shirai, Kazuhito Matsushita, Akira Tsujimura, Shigeo Horie
  • Organizer: American Urological Association Annual meeting
  • Place of Presentation: New Orleans, USA
  • Year and Date: 2015-05-21
• [Presentation] Testosterone gel treatment significantly ameliorates urinary urgency and sleep disturbance: double-blind, placebo-controlled clinical trial. (2015)
  • Author(s): Hisasue S, Ide H, Tsujimura A.
  • Organizer: American Urological Association (AUA) meeting,
  • Place of Presentation: New Orleans, USA
  • Year and Date: 2015-05-05
  • Int'l Joint Research
• [Presentation] Relationship between erectile dysfunction and silent myocardial ischemia in diabetic patients: Detection with multidetector computed tomography coronary angiography (2015)
  • Author(s): Amr Abdelhamed, Shin-ichi Hisasue, Essam A. Nada, Ali A Kassem, Mohammed Abdel-Kareem, Shigeo Horie
  • Organizer: 日本泌尿器科学会総会
  • Place of Presentation: 金沢、日本
  • Year and Date: 2015-04-19