2014-12-012024-05-14https://scholars.lib.ntu.edu.tw/handle/123456789/656505摘要：多囊性卵巢症候(PCOS)是發生在5%-10%生育年齡之女性的常見內分泌疾病，表現之症狀為月經不規則、不排卵、雄性素過高、多囊性卵巢，以及不孕症。PCOS之病人還常併發代謝症候群，而且有較高的危險罹患精神疾病與阿茲海默症(AD)。PCOS之發病機制不完全清楚，但卵巢雄性素過高，高胰島素血症，以及神經內分泌失能都被認為是病因之一。近來的研究現顯示卵巢顆粒細胞與濾泡膜細胞之失能分別造成濾泡之不正常形成以及雄性素過高；PCOS之卵巢異常已知與神經內分泌細胞失能有關，其特徵是促性腺激素釋放素之脈動增加，刺激腦下垂體較偏向分泌黃體激素而不利濾泡激素分泌，而進一步增加卵巢雄性素之製造。由於阿茲海默症在PCOS有較高之罹患率，而且神經內分泌細胞之失能對PCOS之核心症狀影響甚大，因此PCOS之神經細胞與神經內分泌細胞之特色將是本研究之重點之一。雖然PCOS是複雜且多樣的疾病，家族研究強烈支持這是一種遺傳性疾病，已有數個易感性基因座被發現與PCOS有重要相關，但未有一真正之致病基因真的在較大族群中被確認過。目前對PCOS之治療大致以症狀治療為主，這是否真能降低未來因為代謝症候群引起之嚴重疾病的罹患率尚未可知。目前PCOS之動物模式尚未臻理想，部分可能因為小/大鼠與人類的生理仍有差異所致。誘導型多功能幹細胞 (iPSC) 技術的出現已使得研究者可以在培養皿中模擬許多複雜性人類疾病。我們的研究群與中研院之學者合作，也已成功地製造出人類龐貝氏症與卵巢早衰症之專一性iPSCs，並且也觀察到數種藥物對它們之效果。近來我們的研究群更進一步發展出一種可將ESCSs/iPSCs有效地分化成類顆粒細胞的方法，可使PCOS之體外表現型之分析更為容易。因此，我們假設: 利用一定數量之台灣的PCOS病人之細胞做成之iPSCs，可以用來在體外再現疾病之表現型，並用來研究PCOS之致病機轉。再者，神經與神經內分泌細胞以傳統方式是極難取得的，而PCOS之iPSCs則可以提供研究它們之珍貴機會，並且也可用來驗證PCOS腦中之異常是否為一種細胞自主現象。最後，我們在此已提出與具有豐富藥物篩選經驗之另一子計畫主持人合作之藍圖，勢必將大幅增進找出反轉PCOS表現型之藥物的腳步。在達成以上這些具體小目標後，我們必定可以對台灣的PCOS之致病機制有進一步的深刻了解，並據以達到發展更好、且更安全治療的終極目的。<br> Abstract: Polycystic ovary syndrome (PCOS) is a common endocrine disorder occurring in 5%-10% of women of reproductive age, manifested by menstrual irregularity, anovulation, hyperandrogenism, polycystic ovaries, and infertility. Patients with PCOS are often complicated by metabolic syndromes and have a higher risk of developing psychiatric diseases and Alzheimer disease (AD). The pathogenesis of PCOS is not clear, although ovarian hyperandrogenism, hyperinsulinemia, and neuroendocrine dysfunction are all considered to be etiological factors. Recent studies have suggested that dysfunction of granulosa cells and theca cells contribute to the abnormal folliculogenesis and hyperandrogenism in PCOS, respectively. Ovarian abnormalities in PCOS have been linked to neuroendocrine dysfunction, characterized by increased pulsatility of gonadotrophin-releasing hormone (GnRH), which favors pituitary synthesis of luteinizing hormone (LH) over that of follicle stimulating hormone (FSH) and further augments ovarian androgen synthesis. Since the incidence of AD increases in PCOS patients, and neuroendocrine dysfunction contribute greatly to the core manifestations of PCOS, the feature of neurons and neuroendocrine cells of PCOS will be one key point of our research interest. Although PCOS is a complex and heterogeneous disorder, family studies strongly support that it is a genetic disease, with several susceptibility loci significantly associated with PCOS but without any definite disease-causing gene being confirmed in a large population of patients. The current treatment for PCOS is largely symptomatic; whether it can reduce the future incidence of severe diseases caused by metabolic disturbances is still unclear.So far, an ideal animal model for PCOS is still lacking, partially because of the discrepancy in physiology between mice/rats and humans. With the advent of the technique of induced pluripotent stem cells (iPSCs), researchers started to have the opportunity to model complex human diseases in culture dishes. It has been published that disease-specific iPSCs can be used as efficient platforms to screen novel therapeutic reagents for several diseases. Our group, with previous collaboration with researchers in Academia Sinica, has also successfully derived disease-specific iPSCs from human Pompe disease and POF, and has observed the therapeutic effect of selected drugs on them. Furthermore, recently our group has successfully developed a method to efficiently differentiate human ESCs/iPSCs into granulosa-like cells, making the in vitro PCOS phenotypes analysis more feasible. Therefore, we hypothesize that iPSCs from a significant number of PCOS patients in Taiwan, can be use to recapitulate the disease phenotypes in vitro and to study the specific pathogenesis of PCOS in Taiwan. PCOS-iPSCs also provide a valuable opportunity to investigate the disease phenotypes in neurons and neuroendocrine cells, which are rarely accessible by other traditional methods, and to determine whether these abnormalities in the brain are cell-autonomous. Moreover, we propose that by a collaboration of the PI of another sub-project, who has much experience and resources in drug screening, we will be able to identify novel drugs that can reverse these phenotypes. By achieving these objectives, we will make a considerable progress on the understanding of PCOS pathogenesis in Taiwan and ultimately attain the goal of developing a better and safer treatment for these patients.多囊性卵巢症候群顆粒細胞神經內分泌細胞誘導型多能幹細胞polycystic ovary syndromegranulosa cellsneuroendocrine cellsinduced pluripotent stem cells