PROJECT 3 - THECA CELL FUNCTION IN POLYCYSTIC OVARY SYNDROME

项目 3 - 多囊卵巢综合征中的卵泡膜细胞功能

基本信息

批准号：
8053731
负责人：
R JEFFREY CHANG
金额：
$ 40.37万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/8053731
关键词：
2,4-thiazolidinedione Accounting Adipose tissue Adrenal Glands Affect Age Agonist Androgens CYP17A1 gene Cell physiology Clinical Coculture Techniques Corticotropin Diazoxide Disease Dose Dyslipidemias Exhibits Functional disorder Gonadotropins Hirsutism Human Human Chorionic Gonadotropin Hyperinsulinism In Vitro Individual Infusion procedures Insulin Insulin Resistance Intention Measures Metabolic Modality Molecular Morphology Non obese Obesity Ovarian Ovarian Ablation Pathway interactions Patients Phenotype Physiological Pioglitazone Pituitary Gland Pituitary Gonadotropins Polycystic Ovary Syndrome Process Production Recovery Relative (related person)Role Serum Stem Cell Factor Steroid biosynthesis Steroids System Testing Thiazolidinediones Woman desensitization design granulosa cell improved in vivo inhibin insight insulin secretion insulin sensitivity novel novel strategies paracrine reproductive response theca cell translational study

项目摘要

Polycystic ovary syndrome (PCOS) affects 5-10% of reproductive-aged women. Essentially all suffer rom excess ovarian androgen production which causes hirsutism and likely perpetuates multiple eproductive and metabolic disruptions associated with the disorder, including altered pituitary gonadotropin secretion, morphologic and functional ovarian abnormalities, altered adipose distribution, insulin resistance, and dyslipidemia. However, a comprehensive understanding of the mechanisms that dictate androgen overproduction is lacking, which may account for inconsistencies between measures of androgen excess and clinical presentation in individual cases. The need for detailed translational studies is underscored by the limited response to treatment of androgen excess in these patients. We hypothesize that in PCOS theca cell (TC) androgen production is influenced by a variety of extra- as well as intra-ovarian factors, although the relationships among these factors are not well understood. Accordingly, we will assess in detail the mpact of increased LH secretion, in vivo and in vitro paracrine influences by the granulosa cell (GC), and the role of hyperinsulinemia on TC function. In addition, consideration of altered steroidogenic pathways to hyperandrogenemia will be explored with respect to the integrity of GC function, adrenal androgen production, and insulin secretion, all of which are implicated in androgen overproduction in PCOS. Initially, the ED5o for hCG-stimulated TC response will be determined and subsequently used to test the roles of LH secretion including pulsatile release, FSH-stimulated GC paracrine factors, and increased (insulin infusion) and decreased (diazoxide) insulin levels. Delta-4 and -5 steroid pathways will be assessed among PCOS women that exhibit high and normal 17OHP responses to hCG relative to contributions of GCs (FSH stimulation), adrenal androgens (ACTH infusion), and insulin (diazoxide) that may be responsible of this disparity. In vitro, we will assess the molecular and cellular paracrine mechanisms by which GC-derived inhibin and kit ligand enhance TC androgen production using the human TC/GC primary co-culture system. The proposed studies will begin to delineate the multiple influences that drive excess ovarian androgen production and, hopefully, provide insight into novel and targeted treatment modalities for women suffering from PCOS.

多囊卵巢综合症 (PCOS) 影响 5-10% 的育龄妇女。基本上所有人都受苦卵巢雄激素产生过多，导致多毛症并可能使多毛症永久存在与该疾病相关的生殖和代谢紊乱，包括垂体促性腺激素的改变分泌、卵巢形态和功能异常、脂肪分布改变、胰岛素抵抗、和血脂异常。然而，对决定雄激素的机制的全面了解缺乏过量生产，这可能是雄激素过量测量之间不一致的原因以及个别病例的临床表现。强调了进行详细转化研究的必要性这些患者对雄激素过多治疗的反应有限。我们假设在 PCOS 中卵泡膜细胞（TC）雄激素的产生受到多种卵巢外和卵巢内因素的影响，尽管这些因素之间的关系尚不清楚。据此，我们将详细评估 LH 分泌增加的影响，颗粒细胞 (GC) 的体内和体外旁分泌影响，以及高胰岛素血症对 TC 功能的作用。此外，考虑改变类固醇生成途径将探讨高雄激素血症与 GC 功能的完整性、肾上腺雄激素的关系产生和胰岛素分泌，所有这些都与多囊卵巢综合征中雄激素的过量产生有关。最初，将确定 hCG 刺激的 TC 反应的 ED50，并随后用于测试 LH 的作用分泌包括脉冲释放、FSH 刺激的 GC 旁分泌因子和增加（胰岛素输注）并降低（二氮嗪）胰岛素水平。将在 PCOS 中评估 Delta-4 和 -5 类固醇途径相对于 GC（FSH 刺激）的贡献，对 hCG 表现出高且正常 17OHP 反应的女性，肾上腺雄激素（ACTH输注）和胰岛素（二氮嗪）可能是造成这种差异的原因。在体外，我们将评估 GC 衍生的抑制素和试剂盒配体使用人类 TC/GC 初级共培养系统增强 TC 雄激素的产生。拟议的研究将开始描述导致卵巢雄激素分泌过多的多重影响希望能为患有 PCOS 的女性提供新颖且有针对性的治疗方式的见解。