2015-08-012024-05-17https://scholars.lib.ntu.edu.tw/handle/123456789/670885摘要：多囊性卵巢症候群是一個在生殖內分泌與不孕症醫學領域十分重要的疾病，其發生率高達6-10%，可說是育齡婦女最常見的內分泌障礙，也是造成不孕症的重要原因之一。儘管這個疾病如此普遍而重要，然而其致病機轉至今仍未明，導致不管是在診斷及治療上都進展有限。在過去的研究中認為，最重要的致病機轉之一為卵巢雄性荷爾蒙的過量產生，而根據動情素合成假說“Two-cell two-gonadotropin theory”，卵巢的髓鞘細胞(theca cell)接收到腦下垂體分泌之黃體刺激素(luteinizing hormone)刺激後，會分泌雄性荷爾蒙，因此卵巢高雄性荷爾蒙病症的產生，與卵巢的髓鞘細胞之功能應具有高度相關性。儘管髓鞘細胞在多囊性卵巢症候群的致病機轉扮演著極為關鍵的角色，但到目前為止針對人類髓鞘細胞的研究卻十分有限，主要原因之一就是組織來源取得極為困難。髓鞘細胞位於濾泡基底膜外側，即便是侵入性的取卵手術也只能取得濾泡內的顆粒細胞(granulosa cell)而無法取得髓鞘細胞，過去的研究多半只能利用卵巢手術時取得檢體再進行體外細胞培養，體外培養存活期亦不長因而使得研究困難。因此在本研究計畫中，我們的目的是誘導多囊性卵巢症候群病患之誘導多潛能幹細胞(iPSC)分化成為具有功能性之髓鞘細胞，可建立一個有效的模型來探討卵巢卵髓鞘細胞分化生長、濾泡及卵子之發育成熟、類固醇之製造調控與多囊性卵巢症候群之致病機轉等多項重要議題，更進一步，將多囊性卵巢症候群病患之誘導型多功能幹細胞分化為髓鞘細胞，分析病患髓鞘細胞之基因表現與表觀基因調控(epigenetic regulation)與正常人之不同，期能更加瞭解此疾病，並發展出更佳之診斷模式及具病患專一性之治療方法及藥物篩檢平台，確實地將基礎研究應用於臨床醫療上。<br> Abstract: Polycystic ovarian syndrome (PCOS) is one of the most common endocrine disorders in women of reproductive age which is very important to women’s health. The prevalence is as high as 6-10%. PCOS is characterized by chronic anovulation, menstrual irregularities, polycystic ovaries, and evidences of hyperandrogenism. However its pathophysiology is still unclearand therefore the progress in diagnosis and treatment is limited until nowadays. In previous research, one of the most critical pathophysiology of PCOS was considered to be hyperandrogenism. According to the “two-cell two-gonadotropin theory”, the ovarian androgen is secreted from theca cells after receiving the stimulation of luteinizing hormone released from the anterior pituitary gland. They are fundamental for follicular growth, providing all the androgens required by the developing follicles for conversion into estrogens by the granulosa cells. Therefore the etiology of hyperandrogenism might be highly correlated to the dysfunction or dysregulation of theca cells. Although the theca cells might have important role in PCOS and other hyperandrogenemic disorders, our understanding toward these cells is very limited. Unlike granulosa cells that can be obtained via transvaginal oocyte retrieval surgery during artificial reproductive technique, theca cells are difficult to be retrieved because they are located outside the basal lamina of follicles. Most of previous researches could only get enough theca cells through more invasive surgery for other pathological ovarian disorders. And it is extremely difficult to obtain theca cells from women of PCOS because most of them don’t have surgical indication. Therefore in our research, we would like to differentiate the induced pluripotent stem cells from women of PCOS into theca cells in order to get disease-specific and even patient-specific theca cells. If we could establish a mature model of theca cell differentiation, we might be able to do more research conveniently and have better understand the biogenesis of ovarian steroids hormone, the growth and maturation of follicles, the gene expression and epigenetic regulation of theca cells and granulosa cells, and even the pathogenesis of PCOS. We may also use such cell-based model to establish an effective platform for drug screening and patient-specific therapy.多囊性卵巢症候群髓鞘細胞誘導多潛能幹細胞表觀基因調控polycystic ovarian syndrometheca cellsinduced pluripotent stem cellsepigenetic regulation