Regulation Of Follicle Development and Fertility By Activin and Follistatin

激活素和卵泡抑素对卵泡发育和生育力的调节

• 批准号: 8017367
• 负责人: ALAN L SCHNEYER
• 金额: $ 19.38万
• 依托单位: UNIVERSITY OF MASSACHUSETTS AMHERST
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-02-01 至 2012-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8017367
• 关键词: Activins; Adult; Age; Animal Model; Animals; Apoptosis; Biochemical; Biological; Birth; Breeding; Cell Proliferation; Cyst; Defect; Development; Disease; Elderly; Embryo; Etiology; Failure; Female; Fertility; Fertility Disorders; Fertilization; Follistatin; Foundations; Frequencies; Functional disorder; Future; Genes; Germ Cells; Goals; Growing Follicle; Growth; Human; Infertility; Lead; Left; Litter Size; Mammals; Measures; Meiosis; Menopause; Mus; Neonatal; Oocytes; Ovarian; Ovary; Patients; Premature Ovarian Failure; Primordial Follicle; Process; Property; Protein Isoforms; Regulation; Reproductive Periods; Research; Rest; Role; Site; Staining method; Stains; Superovulation; Syndrome; Technology; Testing; Time; Transgenic Organisms; analog; egg; exhaust; granulosa cell; member; mouse model; neonate; premature; public health relevance; reproductive

DESCRIPTION (provided by applicant): Current evidence supports the long-held concept that the reproductive potential of female mammals is determined by the stock of non-growing, primordial follicles available at birth. These primordial follicles are formed when mitotically active germ cells in cysts cease dividing and arrest in meiosis, after which the cysts break down and some oocytes become surrounded by a few pre-granulosa cells. A small portion of these primordial follicles leave the resting pool each day and develop into growing follicles that eventually produce viable female gametes ready for fertilization. Understanding the biochemical control mechanism for these processes is important as defects could lead to a number of infertility syndromes in humans including premature ovarian failure (POF) in which accelerated loss of follicles is thought to be a possible cause. The factors regulating the processes of cyst breakdown, primordial follicle formation, and activation of primordial follicles are largely unknown but recent advances suggest that activin might be a critical component determining follicle pool size. Activin is a member of the TGF2 superfamily that is regulated by natural antagonists including follistatin (FST). The FST gene produces 3 protein isoforms which have different biochemical properties and biological actions. To determine these actions we created a mouse model in which only the smallest FST isoform, FST288 is made (FST288-only). These mice are subfertile with reduced litter size and frequency. Interestingly, FST288-only females are born with a larger pool of primordial follicles, but these follicles are depleted at a greater rate compared to WT females, suggesting that activin regulates both follicle formation and growth initiation. The broad goal of this proposal is to determine the role of activin in regulating follicle formation, development, and loss. Our central hypothesis is that activin increases germ cell proliferation, reduces apoptosis of oocytes as they form primordial follicles, and increases the number of primordial follicles leaving the resting pool. We propose to determine the mechanism(s) whereby activin regulates follicle formation and loss in Aim 1. The quality of the additional follicles in FST288-only mice will be examined in Aim 2, while in Aim 3 we will test the hypothesis that increased rate of primordial follicle loss leads to POF in FST288-only mice. These results will provide a critical foundation upon which potential applications of activin, activin analogs, or FST antagonists might be developed for treating POF patients. The long term goal of this R21 is to establish endogenous activin and its regulation by FST as critical determinants of follicle pool size and rate of decline with age, which could be relevant for understanding and treating the pathophysiology of POF and other infertility syndromes in humans. Results from the proposed research would also support future projects to use targeted and regulatable transgenic technology to control the site and timing of activin expression that will directly test activin's reproductive roles. PUBLIC HEALTH RELEVANCE: The number of eggs that female animals and humans are born with is their entire stock for their reproductive lifetime. When this stock is depleted, the ovary stops maturing new eggs, a process known as menopause in humans. In some fertility disorders, this process occurs earlier than expected, shortening the reproductive period for these patients and leaving them with few treatment options. The research in this proposal will investigate the role of activin and follistatin in regulating both the number of eggs, and the process of maturation, which could help define the defects that lead to early menopause, and to new treatments for this disorder.

描述（由申请人提供）：当前的证据支持了以下概念，即女性哺乳动物的生殖潜力取决于出生时可用的非生长，原始卵泡的库存。当囊肿中的有丝分裂活性生殖细胞在减数分裂中停止并停止时，会形成这些原始卵泡，然后囊肿分解，一些卵母细胞被一些颗粒前细胞包围。这些原始卵泡中的一小部分每天都会离开静止池，并发展成为成长中的卵泡，最终产生可行的女配子，准备接受施肥。了解这些过程的生化控制机制很重要，因为缺陷可能导致人类中多种不育综合症，包括早产卵巢衰竭（POF），其中加速卵泡被认为是可能的原因。调节囊肿分解过程，原始卵泡形成和激活原始卵泡的因素在很大程度上是未知的，但最近的进步表明，激活素可能是确定卵泡池尺寸的关键成分。激活素是TGF2超家族的成员，该成员受到包括Follistatin（FST）在内的天然拮抗剂的调节。 FST基因产生3种具有不同生化特性和生物学作用的蛋白质同工型。为了确定这些动作，我们创建了一个鼠标模型，其中仅制造了最小的FST同工型（仅FST288）。这些小鼠是子系，垫料的大小和频率降低。有趣的是，与WT女性相比，仅FST288的女性天生具有更大的原始卵泡，但这些卵泡的速率更高，这表明激活素调节卵泡的形成和生长启动。该提案的广泛目标是确定激活素在调节卵泡形成，发育和损失中的作用。我们的中心假设是，激活素会增加生殖细胞增殖，减少卵母细胞形成原始卵泡的凋亡，并增加离开静止池的原始卵泡的数量。我们建议确定激活素在AIM 1中调节卵泡形成和损失的机制。将在AIM 2中检查仅FST288的仅限小鼠中其他卵泡的质量，而在AIM 3中，我们将测试以下假设：Primordial卵泡损失率增加了FST288888888的POF。这些结果将为激活素，激活素类似物或FST拮抗剂的潜在应用提供至关重要的基础，以治疗POF患者。该R21的长期目标是建立内源性激活素及其对FST的调节，作为卵泡池大小的关键决定因素和年龄的下降速率，这可能与人类中POF和其他不育综合症的病理生理学有关。拟议的研究的结果还将支持未来的项目，以使用靶向和可调节的转基因技术来控制激活素表达的位点和时间，该技术将直接测试激活素的生殖作用。 公共卫生相关性：女性动物和人类出生的鸡蛋数量是其生殖寿命的全部库存。当这种股票耗尽时，卵巢停止成熟新卵，这是人类更年期的过程。在某些生育障碍中，此过程比预期的早发生，从而缩短了这些患者的生殖期，并使他们几乎没有治疗选择。该提案中的研究将研究激活素和卵泡蛋白在调节卵子数量以及成熟过程中的作用，这可以帮助定义导致早期更年期的缺陷，以及对这种疾病的新治疗方法。