Role of Fetal Steroids in Formation and Activation of Bovine Ovarian Follicles

胎儿类固醇在牛卵巢卵泡形成和激活中的作用

基本信息

批准号：
7906970
负责人：
JOANNE E. FORTUNE
金额：
$ 19.06万
依托单位：
CORNELL UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-08-15 至 2013-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7906970
关键词：
Achievement Affect Agonist Animal Model Cattle Cells Competence Contraceptive methods Data Development Diplotene Stage Domestic Animals Estradiol Estradiol Receptors Estrogen Nuclear Receptor Estrogen Receptors Experimental Models Exploratory/Developmental Grant Female Fertility Fetus Funding Germ Cells Growth Human In Vitro Individual Left Life Mammals Mediating Meiosis Meiotic Prophase I Modeling Mus Neonatal Oocytes Oogonia Ovarian Ovarian Follicle Ovary Ovulation Play Pregnancy Primates Primordial Follicle Process Production Progesterone Rattus Regulation Rest Rodent Role Ruminants Sheep Signal Pathway Signal Transduction Source Staging Steroids System Testing Testis Testosterone Time Work base critical period fetal granulosa cell in vivo male novel premature prevent public health relevance reproductive reproductive success research study response steroid hormone

项目摘要

DESCRIPTION (provided by applicant): Establishment of a stockpile of primordial follicles, capable of initiating growth and potentially developing to the preovulatory stage, is a prerequisite for female reproductive success. However for non-rodent species, nothing is known about the regulation of these critical steps in gonadal development. In cattle, sheep, and other large mammals, including humans, primordial follicles form over a number of weeks during fetal life, in contrast to their synchronous post-natal development in mice and rats. In addition, in ruminant and primate species no primordial follicles leave the resting pool (activate) for several weeks after follicle formation begins, in contrast to the rapid activation of a subset of newly formed primordial follicles in neonatal rat and mouse ovaries. The ovaries of fetal cattle and sheep actively synthesize steroid hormones, especially in the period before and, to a lesser extent, during follicle formation and estradiol receptors have been localized to both somatic and gametogenic cells. We have developed experimental models in which formation of bovine primordial follicles and development of their capacity to activate (i.e., to initiate growth in response to a stimulator) occur in vitro. Our preliminary data suggest the overall hypothesis of this R21 application: that steroids produced by the fetal bovine ovary, particularly estradiol and progesterone, regulate both follicle formation and the competence of follicles to be activated. We propose three specific aims to test this novel hypothesis. In Specific Aim #1, experiments to test the hypothesis that a decline in ovarian production of estradiol, and perhaps progesterone, initiates or allows follicle formation in vivo are proposed. We propose experiments in Specific Aim #2 to test the hypotheses that ovarian steroids (estradiol and progesterone) prevent the premature activation of newly formed primordial follicles and that they do this by inhibiting or regulating the progression of prophase I of meiosis (bovine primordial follicles form before the oocyte has reached meiotic arrest in the diplotene stage of prophase I). According to our working model, the gradual decline in ovarian production of estradiol and progesterone, just before and during the time when primordial follicles are forming, first allows follicle formation to occur and then promotes the development of follicular competence to activate. In Specific Aim #3, we will begin to determine signaling pathways that subserve the effects of steroids on follicular formation and competence to activate. Together these experiments will provide new information about the regulation of a critical period in ovarian development, in a species that provides an excellent, non-primate model for human ovarian development. PUBLIC HEALTH RELEVANCE: In mammalian females, a pool of primordial ovarian follicles is formed during fetal or neonatal life and since this stockpile of follicles is used through the female's reproductive life as a source of oocytes for ovulation, it is critical for reproductive success and also a potential target for fertility enhancement or contraception. In large mammals, such as cattle, sheep and primates (including humans) the primordial follicles form when the female is a fetus and virtually nothing is known about what regulates this process. We propose to use cattle as an animal model to test the hypothesis that steroids made by the fetal ovary play a role in regulating these earliest stages of ovarian follicular development.

描述（由申请人提供）：建立一大批原始卵泡，能够启动生长并有潜在地发展到卵石前的阶段，这是女性生殖成功的先决条件。但是，对于非变形物种，对性腺发育中这些关键步骤的调节一无所知。在胎儿生命的数周内，在牛，绵羊和其他大型哺乳动物（包括人类）中，与它们同步的小鼠和大鼠同步产后发育形成了鲜明对比。此外，与反刍动物和灵长类动物物种无原始卵泡在卵泡形成后几周离开静止池（激活），与新生大鼠和小鼠卵巢中新形成的原始卵泡的一部分快速激活相反。胎牛和绵羊的卵巢积极合成类固醇激素，尤其是在卵泡形成和雌激素期间和雌二醇受体期间的卵巢和雌二醇受体中，已经定位于体细胞和配子源细胞。我们已经开发了实验模型，在该模型中，牛原始卵泡的形成及其激活能力的发展（即，以响应刺激剂的启动生长）在体外发生。我们的初步数据表明，该R21应用的总体假设是：胎牛卵巢产生的类固醇，尤其是雌二醇和孕酮，调节卵泡形成以及要激活卵泡的能力。我们提出了三个特定的目标，以检验这一新假设。在特定的目标＃1中，提出了雌二醇和孕酮的卵巢产生下降的假设的实验，提出了在体内启动或允许卵泡形成的假设。 We propose experiments in Specific Aim #2 to test the hypotheses that ovarian steroids (estradiol and progesterone) prevent the premature activation of newly formed primordial follicles and that they do this by inhibiting or regulating the progression of prophase I of meiosis (bovine primordial follicles form before the oocyte has reached meiotic arrest in the diplotene stage of prophase I).根据我们的工作模型，雌二醇和孕酮的卵巢产生逐渐下降，就在原始卵泡形成之前和期间，首先允许发生卵泡形成，然后促进卵泡能力的发展以激活。在特定的目标＃3中，我们将开始确定信号通路，这些信号通路能够确定类固醇对卵泡形成和激活能力的影响。这些实验将共同提供有关卵巢发育中关键时期的调节的新信息，该物种为人类卵巢发育提供了出色的非青调模型。公共卫生相关性：在哺乳动物的女性中，在胎儿或新生儿生活中形成了原始卵巢卵泡池，并且由于这种卵泡的储存是通过女性的生殖寿命来使用的，作为排卵的卵母细胞的来源，它对于生殖成功至关重要，也是潜在的生育目标，也是增强或逆势的潜在目标。在大型哺乳动物中，例如牛，绵羊和灵长类动物（包括人类），当雌性是胎儿时，原始卵泡形成了，几乎没有什么能调节这一过程的知识。我们建议将牛作为动物模型来检验以下假设：胎儿卵巢制造的类固醇在调节这些最早的卵巢卵泡发育中起作用。