THE IN VITRO MODELS OF HUMAN OVARIAN FOLLICLE HEALTH AND DISEASE

人类卵巢卵泡健康和疾病的体外模型

• 批准号: 7490118
• 负责人: Teresa K Woodruff
• 金额: $ 28.4万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-04-23 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7490118
• 关键词: Activins; Address; Adult; Age; Alginates; Androgens; Applications Grants; Automobile Driving; BMP15 gene; Back; Basement membrane; Biochemical; Biology; Biomechanics; Biophysics; Birth; Birth Rate; Cell Density; Cell Differentiation process; Cell Proliferation; Cell physiology; Cells; Condition; Cortex of ovary; Coupled; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Depth; Development; Dimensions; Disease; Encapsulated; Endocrine; Environment; Estrogens; Event; Extracellular Matrix; Extracellular Matrix Proteins; Feeds; Fertility; Fetus; Fibroblast Growth Factor 2; Genes; Genetic; Genetic Screening; Germ Cells; Gonadal structure; Gonadotropins; Growth; Growth Differentiation Factor 9; Health; Homeostasis; Hormone Receptor; Hormones; Human; Hydrogels; In Vitro; Individual; Infertility; Knockout Mice; Life; Luteinizing Hormone; Measures; Mechanics; Menarche; Menopause; Methods; Modeling; Molecular; Mus; Muscle Rigidity; Numbers; Oocytes; Ovarian; Ovarian Diseases; Ovarian Follicle; Ovarian Inhibin; Ovary; Pathway interactions; Phenotype; Physical environment; Physiological; Pilot Projects; Pituitary Gland; Platelet-Derived Growth Factor; Polycystic Ovary Syndrome; Population; Premenopause; Primates; Primordial Follicle; Process; Production; Progesterone; Proliferating; Proteins; Range; Recruitment Activity; Regulation; Regulatory Pathway; Reproductive Health; Research Proposals; Role; Science; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Sister; Somatic Cell; Staging; Stem Cell Factor; Steroids; Stromal Cells; Structure-Activity Relationship; Syndrome; Testing; Thinking; Time; Tissues; Translating; Universities; Week; Woman; Women' s Role; Work; base; blastocyst; bone morphogenic protein; concept; day; density; egg; exhaust; granulosa cell; human disease; human tissue; in utero; in vitro Model; in vivo; inhibin; innovation; insight; mouse model; mullerian-inhibiting hormone; oocyte maturation; ovulation time; paracrine; peptide hormone; physical property; poor egg quality; proliferative phase Menstrual cycle; promoter; receptor; reproductive; reproductive axis; response; size; theca cell

The Dual Role of Ovarian Follicles in Human Health and Disease The total number of follicle-enclosed oocytes in the ovary is set at birth.5 In a 20 week human fetus, there are approximately 7-8 million oocytes in the immature gonad. The most rapid period of oocyte loss occurs in utero and only 1 million oocytes remain in the ovary at birth. After birth, the rate of oocyte loss slows and is quite steady, with a gradual loss to a population of about 400,000 oocytes at the time of menarche. Less than 500 of the 400,000 oocytes eventually ovulate in an ordered or methodical fashion. The follicle serves two roles in the adult: it provides the potential for sexual propagation and produces appropriate levels of steroid and peptide hormones to control reproductive and non-reproductive tissue function. Normal follicle selection occurs in response to folliclestimulating hormone (FSH) action on preantral follicles that express sufficient levels of the FSH receptor (FSHR) via stimulation of intracellular cAMP levels.6 Subsequent activation of the PKA signal transduction pathway causes a switch in SF-1-LRH1 occupancy on the inhibin a-subunit promoter, resulting in the production of ovarian inhibin (and see Project II for an in-depth description of this regulatory pathway).1'7 Inhibin feeds back to the pituitary and blocks a constitutive activin signal, thereby reducing circulating FSH levels to pre-surge levels (and see Project III for an in depth description of activin and its interaction with its receptor).1'8"11 The granulosa cells then proliferate in conjunction with final cytoplasmic maturation of the oocyte, culminating in the release of a fertilizable egg at the time of ovulation (see Project /for details on the regulation of the ovarian follicle signaling pathways controlling coordinated granulosa cell-oocyte maturation). The release of a fertilizable oocyte is the defining role of the female reproductive axis. The inability to recruit or mature good quality gametes contributes to human infertility. Unlike any other process in the body, the maturation of eggs is time delimited and must occur before the supply of follicles is exhausted at menopause. Moreover, egg quality diminishes with time, and in some women, both the quantity and quality of the follicleenclosed egg is reduced more quickly than chronological age alone would predict. This phenomenology creates the dual problems of infertility (in those wishing to reproduce) and loss of premenopausal hormone homeostasis. Thus, two major questions are posed, how are individual follicles selected from the large starting pool and what contributes to the quality of their genetic content? Hormones Regulate Follicle Selection There are three phases of follicular development defined by the actions of endocrine hormones and paracrine-acting factors. The initial development of primordial follicles to primary through early secondary stages is generally considered independent of gonadotropin control.12 These stages occur in the absence of FSH and luteinizing hormone (LH), as shown in studies of gonadotropin knockout mice,13' 14 and a hypogonadotropic pituitary mouse model.15 Instead, early follicle assembly, granulosa cell proliferation and oocyte maturation depend on a sequence of local oocyte-, granulosa- and theca cell-derived factors. Neither these factors nor the sequence of events is completely understood. Roughly, it is thought that platelet-derived growth factor (PDGF) and bone morphogenic protein 6 (BMP6) are produced by primordial oocytes and contribute to primordial follicle quiescence.16'1? Developing follicles also produce anti-Mullerian hormone (AMH), which also inhibits primordial follicle activation and development.18 Signals of unknown origin induce BMP15 expression in oocytes, which stimulates granulosa cell proliferation (in all species except mice).19 Additionally, bFGF expression from oocytes upregulates kit ligand (KL) expression in granulosa cells. Kit ligand from granulosa cells in turn stimulates stromal and theca cell growth20"22 and enhances theca cell recruitment from the surrounding stromal cells.23 As a result, theca cells express BMP4/7 and the cells align along a basement membrane of primary and secondary follicles.24'25 At this point in development, the oocyte produces growth differentiation factor 9 (GDF9), which may maintain theca cell .

卵巢卵泡在人类健康和疾病中的双重作用是卵泡封闭的总数 卵巢中的卵母细胞出生时。5在20周的人类胎儿中，大约有7-8百万个卵母细胞 未成熟的性腺。卵母细胞损失最快的时期发生在子宫内，只有100万个卵母细胞保留在 出生时的卵巢。出生后，卵母细胞损失的速度减慢并且相当稳定，逐渐损失 初潮时期约有40万个卵母细胞。最终在400,000个卵母细胞中少于500个 以有序或有条不紊的方式排卵。卵泡在成年人中扮演两个角色：它提供了潜力 为了性传播并产生适当水平的类固醇和肽激素以控制 生殖和非生殖组织功能。正常的卵泡选择是为了响应卵形刺激 激素（FSH）对表达足够水平FSH受体水平的卵泡的激素作用 （FSHR）通过刺激细胞内营地级别。6随后激活PKA信号转导 途径会导致抑制蛋白A-Subunit启动子的SF-1-LRH1占用率的开关，从而导致 生产卵巢抑制素（有关此法规途径的深入描述，请参见项目II）。1'7 抑制素会反馈到垂体中并阻止构型激活素信号，从而减少循环FSH 预先履行级别的水平（并参见项目III有关激活素的深入描述及其与其的相互作用 受体）.1'8” 11然后，颗粒细胞与最终细胞质成熟一起增殖 卵母细胞，在排卵时最终释放可肥料的鸡蛋（有关该鸡蛋的释放 调节卵巢卵泡信号通路，以控制配位颗粒细胞 - 素环成熟）。 可肥大的卵母细胞的释放是女性生殖轴的决定性作用。无法招募或 成熟的优质配子有助于人类的不育。与体内的任何其他过程不同， 卵的成熟时间是划界的，必须在更年期耗尽卵泡耗尽之前发生。 此外，鸡蛋质量随着时间而减少，在某些女性中，卵形质量的数量和质量都会减少 卵的降低比仅按时间顺序年龄的年龄预测的要快。这种现象学 产生不孕症的双重问题（在那些希望再现的人）和绝经前激素的丧失 稳态。因此，提出了两个主要问题，如何从大型开始中选择单个卵泡 池，什么有助于其遗传含量的质量？ 激素调节卵泡的选择，卵泡发育的三个阶段由 内分泌激素和旁分泌作用因子的作用。原始卵泡的初步发展 通常认为初级到早期次级阶段与促性腺激素控制无关。12这些 如促性腺激素的研究所示，在没有FSH和黄体生成激素（LH）的情况 敲除小鼠，13'14和降压垂体小鼠模型。15相反，早期的卵泡组件， 颗粒细胞增殖和卵母细胞的成熟取决于一系列局部卵母细胞，颗粒和 theca细胞衍生的因素。这些因素和事件的顺序都不完全理解。大致， 据认为，产生了血小板衍生的生长因子（PDGF）和骨形态发生蛋白6（BMP6） 通过原始卵母细胞并有助于原始卵泡静止。16'1？发育的卵泡也会产生 抗毛刺激素（AMH），也抑制原始卵泡激活和发育。18 未知来源诱导卵母细胞中的BMP15表达，刺激颗粒细胞增殖（在所有 除小鼠外的物种）.19此外，卵母细胞的BFGF表达上调了试剂配体（KL）的表达 颗粒细胞。颗粒细胞的试剂盒又刺激基质和theca细胞生长20” 22和 增强了来自周围基质细胞的theca细胞募集。23结果，theca细胞表达BMP4/7 细胞沿着原发性和次级卵泡的基底膜对齐。24'25在这一点上 开发，卵母细胞产生生长分化因子9（GDF9），可以维持theca细胞 。