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：
8239462
负责人：
R JEFFREY CHANG
金额：
$ 38.5万
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/8239462
关键词：
2,4-thiazolidinedione Accounting Adipose tissue Adrenal Glands Affect 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 Medicine 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 Science Serum Stem Cell Factor Steroid biosynthesis Steroids System Testing Thiazolidinediones Woman aged 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 from excess ovarian androgen production which causes hirsutism and likely perpetuates multiple reproductive 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 impact 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 ED{50} 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% 的育龄女性。基本上所有人都患有卵巢雄激素分泌过多，导致多毛症，并可能导致与该疾病相关的多种生殖和代谢紊乱，包括垂体促性腺激素分泌改变、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，缺乏对决定雄激素过量产生的机制的全面了解，这可能解释了个体病例中雄激素过量测量与临床表现之间的不一致。这些患者对雄激素过多治疗的反应有限，强调了进行详细转化研究的必要性。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。因此，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，将探讨改变类固醇生成途径导致高雄激素血症的因素，包括 GC 功能的完整性、肾上腺雄激素的产生和胰岛素分泌，所有这些都与 PCOS 的雄激素过量产生有关。最初，将确定 hCG 刺激的 TC 反应的 ED{50}，随后用于测试 LH 分泌的作用，包括脉冲释放、FSH 刺激的 GC 旁分泌因子以及胰岛素水平升高（胰岛素输注）和降低（二氮嗪）。将在 PCOS 女性中评估 Delta-4 和 -5 类固醇途径，这些女性对 hCG 表现出高和正常的 17OHP 反应，相对于 GC（FSH 刺激）、肾上腺雄激素（ACTH 输注）和胰岛素（二氮嗪）的贡献而言，这可能是导致这种差距。在体外，我们将使用人 TC/GC 原代共培养系统评估 GC 衍生的抑制素和试剂盒配体增强 TC 雄激素产生的分子和细胞旁分泌机制。拟议的研究将开始描述导致卵巢雄激素产生过多的多重影响，并希望为患有多囊卵巢综合症的女性提供新颖且有针对性的治疗方式的见解。