The role of Neuropeptide Y in pathophysiology PCOS follicular development failure

• Project/Area Number: 19K24045
• Research Category: Grant-in-Aid for Research Activity Start-up
• Allocation Type: Multi-year Fund
• Review Section: 0906:Surgery related to the biological and sensory functions and related fields
• Research Institution: The University of Tokyo
• Principal Investigator: Urata Yoko 東京大学, 医学部附属病院, 助教 (20572598)
• Project Period (FY): 2019-08-30 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥2,860,000 (Direct Cost: ¥2,200,000、Indirect Cost: ¥660,000); Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: Neuropeptide Y / 多嚢胞性卵巣症候群 / 卵胞発育障害 / 顆粒膜細胞 / アポトーシス / 細胞増殖能 / 卵胞発育

Outline of Research at the Start

多嚢胞性卵巣症候群は無排卵性不妊の女性の80％を占めるが、その卵胞発育障害の病態は解明されておらず、特異的治療法はない。PCOSには免疫学的因子の関与が考えられている。神経ペプチドであるNeuropeptide Y (NPY)は、非肥満PCOS女性の血中濃度が高いことが知られており、NPYのPCOSへの関与が考えられる。 本研究は、NPYが未熟な卵胞に強く発現していること、NPYが卵胞の細胞の細胞増殖能と細胞死を制御していることを既に確認している。本研究では、①PCOS卵巣でのNPYとNPY受容体の発現制御機構と、②PCOS卵巣でのNPYの機能（卵胞発育の制御と、免疫学的機能）を明らかにする。

Outline of Final Research Achievements

<Objectives> PCOS accounts for 80% of anovulatory infertile women, but the pathophysiology of its follicular developmental disorders has not been elucidated and there is no specific treatment method. Neuropeptide Y (NPY), a neuropeptide, is known to have high blood levels in non-obese PCOS women, and NPY may be involved in PCOS. The objective of this study is to clarify (1) the mechanism of regulation of NPY and NPY receptor expression in the PCOS ovary, and (2) the function of NPY in the PCOS ovary. <Result>1.Androgen stimulation did not change NPY and NPY receptor expression in rodent granulosa cells. 2.Chronic androgen stimulation changed the expression of NPY and NPY receptors in rodent granulosa cells.3.Rodent granulosa cells administered with chronic DHT were stimulated with acute NPY, and apoptosis and cell proliferation ability were evaluated. The pattern of apoptosis changed with and without DHT administration.4.NPY concentration of human follicular fluid is under analysis.

Academic Significance and Societal Importance of the Research Achievements

Neuropeptide Yが多嚢胞性卵巣症候群の卵胞発育障害治療における、新規ターゲット分子の可能性が示唆された。

Research Products

• [Journal Article] Induction of aryl hydrocarbon receptor in granulosa cells by endoplasmic reticulum stress contributes to pathology of polycystic ovary syndrome (2021)
  • Author(s): Kunitomi C, Harada M, Kusamoto A, Azhary JM, Nose E, Koike H, Xu Z, Urata Y, Takahashi N, Wada-Hiraike O, Hirota Y, Koga K, Fujii T, Osuga Y.
  • Journal Title: Mol Hum Reprod Volume: 27 Pages: 1-13
  • DOI: 10.1093/molehr/gaab003
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Androgens increase accumulation of advanced glycation end products in granulosa cells by activating ER stress in PCOS (2020)
  • Author(s): Jerilee MK Azhary, Miyuki Harada, Chisato Kunitomi, Akari Kusamoto, Nozomi Takahashi, Emi Nose, Nagisa Oi, Osamu Wada-Hiraike, Yoko Urata, Tetsuya Hirata, Yasushi Hirota, Kaori Koga, Tomoyuki Fujii, Yutaka Osuga
  • Journal Title: Endocrinology Volume: 161 Pages: 1-13
  • DOI: 10.1210/endocr/bqaa015
  • Peer Reviewed / Open Access / Int'l Joint Research