权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

MOLECULAR BIOLOGY OF POLYCYSTIC OVARY SYNDROME

多囊卵巢综合症的分子生物学

基本信息

批准号：
2673948
负责人：
Denis A Magoffin
金额：
$ 26.66万
依托单位：
CEDARS-SINAI MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
1996
资助国家：
美国
起止时间：
1996-08-02 至 2000-07-31
项目状态：
已结题

项目摘要

DESCRIPTION: Polycystic ovary syndrome (PCOS) is the most common reproductive endocrine disease in women of reproductive age. Many serious health problems are associated with PCOS, including infertility, hirsutism, increased pregnancy loss, markedly increased risk for cardiovascular disease and endometrial cancer at a young age. Despite the seriousness of PCOS and the high prevalence of this disorder, the etiology of PCOS remains a mystery. The metabolic profile of the PCOS patient is heterogenous and has led to controversy regarding even the definition of PCOS but the common physiological link in all subtypes of PCOS is a lack of follicle development beyond the early antral stage. Therefore, in order to understand the causes of PCOS and to develop an effective treatment it is critical to understand the mechanisms regulating selection of the dominant follicle in normal women and how these mechanisms are altered in women with PCOS. The studies performed to date lead to the conclusion that there is an endogenous inhibitor of aromatase (P450AROM) in PCOS that is not present in normal follicles. In preliminary studies, we showed that the concentration of 5-alpha-androstane-3,17-dione, a competitive inhibitor of P450AROM activity in human GC, is significantly higher in PCOS than normal follicles. Interestingly, it appears that 5-alpha-A production decreases markedly in dominant follicles, raising the possibility that regulation of 5-alpha reductase activity may play a role in selection of the dominant follicles and the genesis of polycystic ovaries. The overall goals of this proposal are to assess the role of 5-alpha A in the genesis of PCOS and to understand the regulation of 5-alpha reductase mRNA expression and enzyme activity in the ovary. Specific goals are to determine the magnitude of the effects of 5-alpha A on P450AROM activity in PCOS follicles, to determine if P450AROM expression is blocked in PCOS or if P450AROM is expressed but its activity is inhibited, and to determine if there are abnormalities in P45017alpha and P450scc expression in PCOS. The expression of the two 5-alpha-reductase mRNAs and the localization and activities of the two 5-alpha-reductase isoenzymes in normal and PCOS ovaries will be examined. Finally, the regulation of 5 alpha-reductase gene expression in the ovary will be studied. The results of these studies will provide a wealth of important information regarding the molecular biology of normal follicle development and the abnormalities that occur in PCOS. There is a strong probability that this new knowledge could lead directly to novel therapies that may restore reproductive cyclicity and eliminate many of the increased risks for cardiovascular and malignant disease in women with PCOS.

多囊卵巢综合征（PCOS）是一种多囊卵巢综合征。育龄妇女的生殖内分泌疾病。许多严重多囊卵巢综合征与健康问题有关，包括不孕症，多毛症，流产增加，心血管疾病风险显著增加和子宫内膜癌。尽管PCOS的严重性和这种疾病的高患病率，PCOS的病因仍然是一个谜 PCOS患者的代谢特征是异质的，甚至引起了对PCOS定义的争议，但常见的 PCOS的所有亚型的生理联系是缺乏卵泡发育在早期胃窦期之后。因此，为了了解原因，为了开发一种有效的治疗方法，正常女性优势卵泡选择的调控机制以及这些机制在PCOS患者中是如何改变的。研究迄今为止进行的研究得出结论，芳香化酶抑制剂（P450 AROM）在PCOS中不存在于正常毛囊在初步研究中，我们发现， 5-α-雄甾烷-3，17-二酮，P450 AROM活性的竞争性抑制剂在人类GC中，PCOS中的GC显著高于正常卵泡。有趣的是，似乎5-alpha-A的产生在哺乳动物中显著减少，占主导地位的卵泡，提高了调节5-α的可能性，还原酶活性可能在优势卵泡的选择中起作用和多囊卵巢的形成本提案的总体目标评估5-alpha A在PCOS发生中的作用， 5-α还原酶mRNA表达和酶活性调节卵巢具体的目标是确定影响的程度， 5-α A对PCOS卵泡中P450 AROM活性的影响，以确定P450 AROM是否在PCOS中表达被阻断，或者如果P450 AROM表达，但其活性被抑制，并确定是否存在P45017 α和 P450 SCC在PCOS中的表达两种5-α-还原酶的表达 mRNA与两种5-α-还原酶的定位和活性将检查正常和PCOS卵巢中的同工酶。最后卵巢中5 α-还原酶基因表达的调节将是研究了这些研究的结果将提供大量重要的关于正常卵泡发育的分子生物学信息以及多囊卵巢综合征的异常很有可能这一新的知识可以直接导致新的疗法，恢复生殖周期，消除许多增加的风险，心血管和恶性疾病的妇女与PCOS。